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Duration of antidepressant use during pregnancy and risk of major congenital malformations

  • Élodie Ramos (a1), Martin St-André (a2), Évelyne Rey (a3), Driss Oraichi (a4) and Anick Bérard (a5)...
Abstract
Background

Antidepressant use during the gestational period is a controversial topic.

Aims

To determine whether duration of antidepressant use during the first trimester increases the risk of major congenital malformations in offspring of women diagnosed with psychiatric disorders.

Method

A case-control study was performed among women who had been pregnant between January 1998 and December 2002. Data were obtained from a Medication and Pregnancy registry, built by linking three databases from the province of Quebec, and a self-administered questionnaire. Women eligible for this study had to be 15–45 years old at the beginning of pregnancy, have at least one diagnosis of psychiatric disorder before pregnancy, have used antidepressants for ≥ 30 days in the year prior to pregnancy and have a pregnancy ending with a delivery. Cases were defined as any major congenital malformation diagnosed in the offspring's first year of life. Odds ratios, adjusted for relevant confounders, were estimated using logistic regression.

Results

Among the 2329 women meeting the inclusion criteria, 189 (8.1%) infants were born with a major congenital malformation. Duration of antidepressant use during the first trimester of pregnancy was not associated with an increased risk of major congenital malformations: 1–30 days v. 0 day, adjusted OR=1.23 (95% CI 0.77–1.98); 31–60 days v. 0 day, adjusted OR=1.03 (95% CI 0.63–1.69); ≥ 61 days v. 0 day, adjusted OR=0.92 (95% CI 0.50–1.69).

Conclusions

These data do not support an association between duration of antidepressant use during the first trimester of pregnancy and major congenital malformations in the offspring of women with psychiatric disorders. These findings should help clinicians decide whether to continue antidepressant therapy during pregnancy.

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Copyright
Corresponding author
Dr Anick Bérard, CHU Sainte-Justine, Research Center, 3175 chemin de la Côte-Ste-Catherine, Montreal, Quebec H3T 1C5, Canada. émail: anick.berard@umontreal.ca
Footnotes
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Declaration of interest

None.

Footnotes
References
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Duration of antidepressant use during pregnancy and risk of major congenital malformations

  • Élodie Ramos (a1), Martin St-André (a2), Évelyne Rey (a3), Driss Oraichi (a4) and Anick Bérard (a5)...
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Re: Are antidepressants safe during pregnancy?

Anick B�rard, Associate Professor of Psychiatry
08 September 2008

Dear Editor,

We want to take the opportunity to reply to Rajkumar and Jacob’s letter to the editor on our above cited paper. The nested case-control approach used in Ramos et al.’s is the most effective design to study rareoutcomes such as major congenital malformations. 1 This is even truer since it was performed in one well established cohort of subjects with pre-pregnancy diagnosed psychiatric disorders. We disagree with Rajkumar and Jacob that a cohort approach would have been better based on the fact thatit lacks power for research in perinatal pharmacoepidemiology. This was clearly apparent when several small human cohort studies published in the 1990s did not suggest an overall increased risk for birth defects with first trimester exposure to any SSRIs but later studies with more efficient designs such as the case-control approach started showing low-to-moderate increased risks for the more commonly occurring birth defects, such as heart defects, neural tube defects, and oral clefts. Therefore, using a cohort approach would have resulted again in a null finding, contrary to Rajkumar and Jacob’s comments.

We excluded pregnancies ending with an abortion or a miscarriage per design since malformation outcomes of these fetuses were not available in the Quebec Pregnancy Registry. We agree that this resulted in prevalent cases of malformations in our study but this is highly comparable to studies performed in similar populations. We do not, however, agree that this methodological choice resulted in biasing our study estimates towardsthe null. Indeed, although Hemels et al.2 reported an association between antidepressant use during pregnancy and the risk of spontaneous abortions,this was based on women’s self-report and likely resulted in an overestimation of the rate of miscarriage and an underestimation of the rate of abortion, hence a significant association.

Major congenital malformations are structural abnormalities that affect the way a person looks and require medical and/or surgical treatment. Minor defects are abnormalities that do not cause serious health or social problems. Major defects were the focus of interest in Ramos et al.’s study, and although the risk of minor malformations is interesting, it is a different research question. Several other authors have previously made this distinction.3, 4

We agree that results from observational studies always need to be interpreted with caution. However, given that from an ethical point of view it is almost impossible to randomize pregnant women to receive medications not known to be safe for the foetus, the collection and follow-up of observational data is the only ethical way to close the knowledge gap between the limited value of animal studies and human pregnancy exposures.

Finally, our study was not designed to look at the effect of the duration of specific antidepressants on the risk of specific major congenital malformation. Therefore, we only looked at duration of antidepressant use during the first trimester of gestation and its risk for major congenital malformations, all types and all malformations combined. Results should be interpreted in this context.

Anick Bérard PhDAssociate ProfessorResearch Chair holder ‘Medications, Pregnancy, and Lactation’Faculty of PharmacyUniversity of MontrealandDirectorResearch Unit on Medications and PregnancyResearch CenterSte-Justine’s Hospital,Montreal, Canada

Élodie Ramos MScFaculty of PharmacyUniversity of MontrealandResearch CenterSte-Justine’s Hospital,Montreal, Canada

Declaration of interest: This study was supported by the Fonds de la Recherche en Santé du Québec (FRSQ, grant number: 6263), the Réseau Québécois de Recherche sur l’Usage des Médicaments (RQRUM), and the FRSQ network of the wellbeing of Children. These funding sources had no role inthe design, analysis, interpretation, and drafting of the manuscript and so, there is no conflict of interest to declare.

1.Hernandez-Diaz S, Hernan MA, Meyer K, et al. Case-crossover and case-time-control designs in birth defects epidemiology. Am J Epidemiol 2003;158(4):385-391.

2.Hemels MEH, Einarson A, Koren G, Lanctôt KL, Einarson TR. Antidepressant use during pregnancy and the rates of spontaneous abortions: A meta-analysis. Ann Pharmacother 2005;39:803-809.

3.Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry 2002;159(12):2055-2061.

4.Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335(14):1010-1015.
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Conflict of interest: None Declared

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Are antidepressants safe during pregnancy?

Anto P Rajkumar, Assistant professor
21 August 2008



Ramos et al 1 report that the use of antidepressant medications by women during the first trimester of pregnancy is not associated with an increased risk for major congenital malformations in their children. The authors have a good database to study this topic but have described and analysed it using a case-control framework. However, they assembled two cohorts, with and without exposure to antidepressants during pregnancy. They then observed the various outcomes in both groups. We calculated the relative risk (RR) for major congenital malformations following use of antidepressants during first trimester of pregnancy as 1.13 (95% CI 0.86-1.48) from their published data. Estimating such relative risk and population attributable risk (5.76%) would have bolstered their arguments, as a cohort design is superior to a case-control strategy. However, we suggest caution in generalising these findings due to two important limitations, which were not acknowledged in their paper. If antidepressants are associated with more spontaneous abortions and more number of minor congenital anomalies, their lack of association with major congenital anomalies will not imply any safety. A previous Meta analysis of 3567 women has established a significantly increased relative risk of 1.45 (95% CI 1.19- 1.77) for spontaneous abortions following use of antidepressants during pregnancy 2. Individual antidepressants such as Selective Serotonin Reuptake Inhibitors 3 and other newer antidepressants 4, 5 have lead to more miscarriages when compared with the unexposed control groups. As Ramos et al have included exclusively the women who had their pregnancies ending in delivery; they do not add any information regarding spontaneous abortions. In another study of 482 pregnant women 6, Fluoxetine caused significantly more prematurity (RR 4.8; 95% CI 1.1- 20.8), more admissions to special care nursery (RR 2.6; 95% CI 1.1- 6.9), worse neonatal adaptation (RR 8.7; 95% CI 2.9- 26.6) after adjusting for all potential confounders. 26.8% infants exposed to fluoxetine had two minor congenital anomalies against 15.7% infants who lacked such exposure (P=0.04). 15.5% infants exposed to fluoxetine had three or more minor congenital anomalies against 6.5% infants who were not exposed to fluoxetine (P=0.03) 6. However, Ramos et al excluded minor congenital anomalies during case ascertainment without any explicit justification. Absence of association between use of antidepressants and major congenital malformations will not make a clinician confident to continue antidepressants during the first trimester of pregnancy, if there are concerns over spontaneous abortions, prematurity and minor congenital anomalies. Hence, we encourage cautious interpretation of these findings as well as judicious use of antidepressants for women of reproductive age during our clinical practice.

References:

1.Ramos E, St-Andre M, Rey E, Oraichi D, Berard A. Duration of antidepressant use during pregnancy and risk of major congenital malformations. Br J Psychitary 2008; 192: 344-350.2.Hemels ME, Einarson A, Koren G, Lanctôt KL, Einarson TR. Antidepressant use during pregnancy and the rates of spontaneous abortions: a metaanalysis. Ann Pharmacother. 2005; 39(5): 803-93.Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, Donnenfeld A, McCormack M, Leen-Mitchell M, Woodland C. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA. 1993; 269(17): 2246-8.4.Djulus J, Koren G, Einarson TR, Wilton L, Shakir S, Diav-Citrin O, Kennedy D, Voyer Lavigne S, De Santis M, Einarson A. Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. J Clin Psychiatry 2006; 67(8): 1280-4.5.Chun-Fai-Chan B, Koren G, Fayez I, Kalra S, Voyer-Lavigne S, Boshier A, Shakir S, Einarson A. Pregnancy outcome of women exposed to bupropion during pregnancy: a prospective comparative study. Am J Obstet Gynecol. 2005; 192(3): 932-6.6.Chambers C, Johnson K, Dick L, Felix R, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996; 335: 1010-5.
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