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

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.

Cardiac dysfunction and prenatal exposure to venlafaxine

“…Three large prospective cohort studies 10, 11, 12 and three meta‐analysis 3, 16, 17 that included the SNRI venlafaxine do not suggest an increased risk of congenital malformations, namely cardiac defects. In addition, a recent Nordic cohort study with emphasis on cardiac birth defects, reinforce these results 18. On the other hand, a retrospective study suggests associations between periconceptional use of venlafaxine and some birth defects, including atrial septal defect and coarctation of the aorta 19.…”

Effect of antidepressants use in pregnancy on foetus development and adverse effects in newborns

“…Antidepressant medications should be discontinued gradually in order not to risk the appearance of withdrawal symptoms. Despite the fact that some antidepressants (fluoxetine and paroxetine) have been linked to an increased risk of birth defects [13,14,42], it should be remembered that depression is a disease which is associated with a high risk of suicide, which is why the decision on discontinuing the treatment should take into consideration the patient's mental state. Moreover, some of the studies resulting in alarming findings on the teratogenic effect of antidepressant medications have failed to take into account other risk factors such as maternal age, and use of other drugs and stimulants.…”

“…1, 2). Fluoxetine and paroxetine are believed to be associated with the highest risk of birth defects [13,14]. However, the available information makes unequivocal assessment of the teratogenic effect of antidepressants impossible.…”

“…Venlafaxine was most commonly used SNRI [12]. To date, they have been treated as a homogenous class of drugs in terms of their teratogenic potential, but over the past year, results of two studies have been published in the British Medical Journal, indicating a possible association between the use of some SSRIs in the first trimester and selected congenital malformations [13,14].…”

Medfødte misdannelser med basis i Medisinsk fødselsregister; tidstrender og mulige sammenhenger

“…Ett eksempel er et stort nordisk prosjekt der en av studiene også så på forholdet mellom legemiddelbruk i svangerskapet og medfødte misdannelser (35). Her ble fødsels-og legemiddelregistre i Norden koblet, og man evaluerte forholdet mellom mors bruk av SSRI og venlafaksin i første trimester og medfødte misdannelser hos avkommet.…”