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Counseling pregnant women treated with paroxetine; Concern about cardiac malformations

Adrienne Einarson, RN Gideon Koren, MD, FRCPC

May 2006



I have always reassured my patients that taking selective serotonin reuptake inhibitors (SSRIs) during pregnancy would not increase their risk of having children with major malformations. A recent warning from Health Canada, based on results of a study from GlaxoSmithKline, stated that infants exposed to paroxetine might be at higher risk of congenital malformations, specifically cardiovascular defects. Some of my pregnant patients who are taking paroxetine heard the warning and asked me whether they should stop taking it. What should I tell them?


The new warning is based on unpublished, non-peer-reviewed studies. It ignored 2 published studies that failed to show any association between exposure to paroxetine and cardiovascular malformations, and no association with cardiovascular malformations has been shown by SSRIs as a class. Even if there is risk, it is minimal, and the warning does not disclose details of the cardiovascular malformations. Many cases of ventricular septal defect, the most common cardiac malformation, resolve spontaneously. Concerned pregnant women should know that, if taken after the first trimester, drugs cannot cause cardiac malformations. Failure to treat depression during pregnancy can have severe consequences for both mothers and babies and is the strongest predictor of postpartum depression.


J'ai toujours rassuré mes patientes que l'administration des inhibiteurs sélectifs du recaptage de la sérotonine (ISRS) durant la grossesse n'augmenterait pas le risque d'avoir des enfants ayant des malformations majeures. Un récent avertissement de Santé Canada, fondé sur les résultats d'une étude par GlaxoSmithKline, indique que les nouveau-nés exposés à la paroxétine pourraient avoir des risques plus élevés de malformations congénitales, en particulier des anomalies cardiovasculaires. Certaines de mes patientes qui prennent de la paroxétine ont entendu cet avertissement et me demandent si elles devraient cesser leur médicament. Que devrais-je leur répondre?


Ce nouvel avertissement se fonde sur des études non publiées qui n'ont pas fait l'objet d'une critique par les pairs. Il ne tenait pas compte de 2 études publiées qui, elles, n'avaient pas établi de lien entre l'exposition à la paroxétine et les malformations cardiovasculaires, ni entre les malformations cardiovasculaires et les ISRS comme classe de médicaments. S'il y a un risque, il est minime et l'avertissement ne divulgue pas les détails des anomalies cardiovasculaires. Plusieurs cas de communication interventriculaire, la malformation cardiaque la plus courante, se règlent d'eux-mêmes. Les femmes enceintes qui s'inquiètent devraient savoir que, s'ils sont pris après le premier trimestre, les médicaments ne peuvent pas causer de malformations cardiaques. L'omission de traiter la dépression durant la grossesse peut avoir de graves conséquences pour la mère et l'enfant et elle est le facteur de prédiction le plus important de la dépression postnatale.

To date, no selective serotonin reuptake inhibitor (SSRI) has been associated with increased risk of major congenital malformations, including cardiovascular anomalies.1 Recently, GlaxoSmithKline (GSK) released an advisory2 that was subsequently incorporated into a Health Canada advisory3 indicating that infants exposed to paroxetine at the time of organogenesis were at a higher risk of congenital malformations, particularly cardiovascular (ventricular septal) defects. This information was based on an unpublished, retrospective, epidemiologic study, conducted by GSK, and 3 abstracts presented at scientific conferences.

The GSK study claimed that the prevalence of major malformations associated with use of paroxetine was 4% overall and that the prevalence of cardiovascular malformations was 2%.2 Alwan et al4 presented a case-control study that showed an increased risk of major malformations in general with SSRIs, but no association with cardiovascular defects. Wogelius et al5 reported a small increase in cardiovascular malformations based on a prescription database study where it was not known whether pregnant women actually took the medication. Finally, Diav-Citrin et al6 presented a prospective comparative study that also showed a small increase in rates of cardiovascular defects (1.9%) associated with use of paroxetine. As these data are based on unpublished, non-peer-reviewed studies, we cannot accept their results as definitive conclusions. It should also be noted that cardiovascular malformations are common in the general population; they occur in approximately 1% of all newborns.

A large proportion of ventricular septal defects (of the muscular type) are considered minor and resolve spontaneously. The data suggest that, even if there is a risk of malformations, it is minimal. As well, it is likely that more tests, including echocardiograms, would be carried out on depressed and anxious women than on non-depressed women, which would create a bias in the rates of cardiac malformations.

An association with cardiovascular malformations has not been found with other SSRI drugs. To date, no evidence has emerged to show that only one agent in a class of drugs is associated with increased risk of birth defects or other adverse effects, while the others are not. For example, all angiotensin-converting enzyme inhibitors have been implicated in causing fetal hypocalvaria, renal defects, and renal failure.7

The suggested association has not been found in previously published studies on paroxetine. Ericson et al8 published a study that included 122 cases of embryonic exposure to paroxetine. There was no difference in rates of cardiovascular defects between paroxetine and control groups. Motherisk published a study of 267 women whose fetuses were exposed to SSRIs in which 2 cardiovascular defects were described. One defect occurred among 97 fetuses exposed to paroxetine, a rate similar to that of the other SSRIs (1/169).9 Also, we re-analyzed our recent meta-analysis of associations between congenital anomalies and SSRIs compared with controls1 and could not detect an increased risk of cardiac malformations associated with SSRIs as a class. Last, a large case-control study from Sweden also failed to show an association between cardiac malformations and SSRIs (odds ratio 0.95, 95% confidence interval 0.62 to 1.44).10

Three published, peer-reviewed studies show no increase in rates of cardiovascular malformations with use of paroxetine.8-10 In 4 recent unpublished reports, no increased risk of cardiovascular malformations was found. Three reports found a small apparent risk.

Failure to treat depression during pregnancy can have severe consequences for both mothers and babies. Most notably, untreated depression during pregnancy is the strongest predictor of postpartum depression, which can sometimes have tragic consequences.11

Women and their physicians should discuss this information and make informed decisions about whether to continue paroxetine during pregnancy (Table 1). Concerned patients can be offered ultrasound and echocardiographic investigations that can detect and rule out fetal cardiac problems in early pregnancy. Antidepressants should never be stopped abruptly12; if women decide, following discussion with their physicians, that they want to discontinue paroxetine, they should taper off dosage slowly over several weeks.


  1. . Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 2005;14(12):823-7.
  2. GlaxoSmithKline. New safety information regarding paroxetine: findings suggest increased risk over other antidepressants, of congenital malformations, following first trimester exposure to paroxetine. GSK advisory September 2005. Mississauga, Ont: GlaxoSmithKline; 2005. Available at: http://www.gsk.ca/en/health_info/PAXIL_PregnancyDHCPL_E-V4.pdf . Accessed 2006 March 23.
  3. GlaxoSmithKline. Health Canada endorsed important safety information on Paxil (paroxetine) and possible increased risk of birth defects. Health Canada advisory October 2005. Ottawa, Ont: Health Canada; 2005. Available at: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2005/paxil_3_hpc-cps_e.html. Accessed 2006 March 23.
  4. Alwan S, Reefhuis J, Rasmussen S, Olney R, Friedman JM. Maternal use of selective serotonin re-uptake inhibitors and risk for birth defects [abstract]. Birth Defects Res A Clin Mol Teratol 2005;73:291.
  5. Wogelius P, Norgaard M, Muff Munk E, Mortensen PB, Lipworth L, Sorensen HT. Maternal use of selective serotonin reuptake inhibitors and risk of adverse pregnancy outcomes [abstract]. Pharmacoepidemiol Drug Saf 2005;14:S72.
  6. Diav-Citrin O, Shechtman S, Weinbaum D, Arnon J, Gianantonio E, Clementi M, et al. Pregnancy outcome after gestation exposure to paroxetine: a prospective controlled cohort study. Presented at the Teratology Society 45th Annual Meeting; 2005 June 25-30; St Pete Beach, Fla.
  7. Briggs G, Freeman R, Yaffe S. Drugs in pregnancy and lactation. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005. p. 553.
  8. Ericson A, Kallen B, Wilholm BE. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 1999;55:503-8.
  9. Kulin NA, Pastuszak A, Sage S, Schick-Boschetto B, Spivey G, Feldkamp M, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA 1998;279:609-10.
  10. Kallen BA, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defects. Reprod Toxicol 2003;17:255-61.
  11. Beck CT. Postpartum depression predictors inventory (revised). Adv Neonat Care 2003;3(1):47-8.
  12. Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counseling. J Psychiatry Neurosci 2001;26(1):44-8.

Motherisk questions are prepared by the Motherisk Team at The Hospital for Sick Children in Toronto, Ont. Ms Einarson is Assistant Director and Dr Koren is Director of the Motherisk Program. Dr Koren is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation and, in part, by a grant from the Canadian Institutes of Health Research. He holds the Ivey Chair in Molecular Toxicology at the University of Western Ontario in London.

Published Motherisk Updates are available on the College of Family Physicians of Canada website (www.cfpc.ca).

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