We found that antidepressant use during pregnancy was associated with a 68% relative increase in the overall risk of spontaneous abortion. Specifically, we observed significant associations with the use of selective serotonin reup-take inhibitors, particularly paroxetine, as well as with venlafaxine. Use of more than one class of antidepressant doubled the risk of spontaneous abortion. Furthermore, we observed an association between a higher mean daily dose of paroxetine or venlafaxine during pregnancy and an increased risk of spontaneous abortion, which is consistent with a dose–response relationship.
Previous studies have produced inconsistent findings. Pastuszak and colleagues reported a nonsignificant increase in the prevalence of spontaneous abortion among pregnant women receiving selective serotonin reuptake inhibitors (14.8%) or tricyclic antidepressants (12.2%) compared with those who did not receive such medications (7.8%).24
Similarly, Djulus and colleagues observed a higher rate of spontaneous abortion among women exposed to mirtazapine or to other antidepressants than among nonusers, but none of the differences was statistically significant.7
In another study, involving 136 women exposed to bupropion early in their pregnancy, Chun-Fai-Chan and colleagues reported more spontaneous abortions in the bupropion group than in the comparison groups.8
In contrast, Chambers and colleagues observed no statistically significant difference in the occurrence of spontaneous abortion between women taking fluoxetine during pregnancy and pregnant women not taking the medication.25
Similarly, Kulin and colleagues observed no significant association between the use of antidepressants during pregnancy and the risk of spontaneous abortion among 92 women who received fluvoxamine in combination with other antidepressants compared with 267 pregnant women not taking antidepressants.26
Three other studies, involving 434 women in total, found no significant association between paroxetine use during gestation and the risk of spontaneous abortion.9,27,28
Einarson and colleagues found no statistically significant association between venlafaxine use during pregnancy and the risk of spontaneous abortion among 150 women.18
Two recent reviews reported contradictory findings.11,12
Gentile did not find a consistent statistically significant association between the use of serotonergic antidepressants during gestation and the risk of spontaneous abortion.11
However, Broy and Bérard, who also included studies published in 2009, reported an increased risk of spontaneous abortion associated with the overall use of antidepressants, specifically paroxetine and venlafaxine.12
Most of the above studies had limitations such as insufficient power; inefficient study design; potential misclassification of study outcome or exposure owing to maternal recall; lack of complete information on exposure including type, timing and dosage of antidepressant; and the inability to fully address potential confounders, especially indication for use of antidepressants.8,11
Nevertheless, our findings are similar to those of Einarson and colleagues, who showed that overall antidepressant use during early gestation increased the risk of spontaneous abortion by 63%.18
Much remains unclear with regard to the exact mechanism of action, although it has been suggested that the effect of selective serotonin reuptake inhibitors on spontaneous abortion is probably mediated by a serotonergic mechanism.29
Strengths and limitations
Our large sample enabled us to evaluate the effect of classes, types and dosages of antidepressants. We also used accurate data on filled prescriptions without having to rely on maternal recall, as well as prospectively and routinely collected data on physician-based diagnoses or procedures related to spontaneous abortions, which limited the potential for detection bias. Gestational age was validated by ultrasound and available in hospital charts as of the index date, which enabled us to calculate the exact timing of exposure to antidepressants during pregnancy. Furthermore, we adjusted our findings for the indication for antidepressant use and the severity of maternal psychiatric disorders by adjusting for variables such as history of depression and anxiety, duration of antidepressant exposure in the year before pregnancy, and the number of visits to a psychiatrist before and during pregnancy. Therefore, we are confident that residual confounding by indication, if present, would not explain our findings. Finally, the nested case–control design permitted us to select controls from the same source population as the cases, which limited the potential for selection bias.
The evaluation of exposure based on filled prescriptions might not have reflected actual intake. However, we hypothesized that women who filled a prescription for an antidepressant took at least one dose, since within the Quebec drug plan, they need to cover part of the cost of their medications. Therefore, given the design of our study, this would not invalidate our findings.
We included only clinically detected spontaneous abortions, without relying on maternal recall. Spontaneous abortions that were never detected by the women themselves were excluded, as was done in other similar studies to date.10,11,18
If the use of antidepressants increases the risk of spontaneous abortions that are not clinically detected, our findings are conservative and thus would underestimate the true risk. However, if there is no association between the use of antidepressants and the risk of spontaneous abortions that are not clinically detected, there is no reason to believe that misclassification would be different between cases and controls, resulting in nondifferential misclassification.
Because we used data from administrative databases, information on potential confounding variables such as smoking and obesity were not available. However, we have previously shown that smoking and maternal weight are not strong enough confounders to reverse findings of associations between use of antidepressants during gestation and adverse pregnancy outcomes.30
Moreover, Einarson and colleagues observed that smoking was not associated with the risk of spontaneous abortion.18
Some evidence suggests that pregnant women with depression are at increased risk of spontaneous abortion,31
which is similar to our findings. Although we adjusted for history of depression, anxiety and use of psychiatric services, we cannot completely exclude the possibility of residual confounding by underlying disease in the risk estimates for venlafaxine or for combined use of more than one class or type of antidepressant, because venlafaxine and antidepressant combinations are most often prescribed in severe cases of psychiatric disorders and in cases of drug-resistant disorders.32
Moreover, given the number of comparisons made in our study, we cannot rule out the possibility of chance findings in 5% of our statistically significant associations.
Finally, even with our large sample, our analyses of specific classes and types of antidepressants may have missed significant associations because of lack of statistical power. Although the risk of spontaneous abortion was higher with the use of selective serotonin reuptake inhibitors during pregnancy than with the use of other antidepressant classes, we did not observe significantly different risks between specific types of selective serotonin reuptake inhibitors. These results, which suggest an overall class effect of selective serotonin reuptake inhibitors, are highly robust given the large number of users studied. However, comparisons with other selective serotonin reuptake inhibitors or tricyclic antidepressants or other antidepressants alone are less robust because of smaller numbers of users.
The use of antidepressants during pregnancy, especially paroxetine and venlafaxine, as well as the combined use of more than one class or type of antidepressant, was associated with an increased risk of clinically detected spontaneous abortion in our study population. In addition, we observed an association between a higher mean daily dose of paroxetine or venlafaxine during pregnancy and an increased risk of spontaneous abortion, which is consistent with a dose–response relationship. In light of our results, physicians who have patients of child-bearing age taking antidepressants or have pregnant patients who require antidepressant therapy early in pregnancy may wish to discuss the risks and benefits with them.