Is too much caution enough?

DSM Digest

Over the past 10 years, increased attention has been paid to depression in pregnancy, whether a new episode of depression or a pre-existing depressive illness. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) recognises this new emphasis on depression in pregnancy with the replacement of the former post-partum specifier (in DSM-IV) with a peripartum specifier that allows for coding, ‘if onset of mood symptoms occurs during [emphasis added] pregnancy or in the four weeks following delivery’ (American Psychiatric Association, 2013).

The use of antidepressant medications, especially selective serotonin reuptake inhibitors (SSRIs), has become widespread and many women have conceived while taking them, prompting studies evaluating their safety. A major focus, quite naturally, has been on whether fetal exposure increases the risk of congenital abnormalities, a critically important issue following the discovery of the teratogenic effects of thalidomide. In this issue of the Australian and New Zealand Journal of Psychiatry, Myles et al. (2013) provide us with a systematic review of first-trimester fetal exposure to SSRIs and the risk of congenital malformations. This review, like several others, identified a small, but significantly increased risk for congenital malformations associated with SSRIs (odds ratio: 1.10), with two agents, fluoxetine and paroxetine contributing to this risk.

It is important to emphasise that while this is a statistically increased risk, the absolute risk of congenital malformation associated with SSRIs remains very low. Studies on congenital abnormalities associated with first-trimester exposure to SSRIs have produced inconsistent results, with some studies reporting an increased risk, whereas others have not, depending on the type of study and the sample size. The most consistent finding relates to the risks associated with exposure to paroxetine.

An obvious conclusion from this paper, and from the other meta-analyses, is that the SSRIs are safe to use in pregnancy. After all, the major concern about fetal exposure to drugs is the risk of congenital malformation. This can be reassuring for clinicians who are already treating women with antidepressants when they conceive and who are concerned about the safety of continuing the antidepressants, especially when it has been demonstrated that there is a high risk of relapse if the antidepressants are withdrawn (Cohen et al., 2006).

While the risks of fetal exposure to antidepressant medications are an important consideration, they need to be balanced against the possible impact of maternal depression on the course of pregnancy and fetal development. Maternal depression has been associated with small, but statistically significant risks of premature delivery, low birth weight and low uptake of breastfeeding (Grigoriadis et al., 2013a), and suggestions that it may have an adverse impact on infant emotional and cognitive development (Chaudron, 2013). Such findings emphasise the importance of recognising, and treating, depression in pregnancy.

But is it as straightforward as that? There are three other important issues that need to be taken into account.

The first issue relates to SSRIs having other effects on the developing fetus and the course of pregnancy that need to be considered. First, infants have a significantly increased risk of a poor neonatal adaptation syndrome characterised by symptoms of respiratory distress, tremors, shaking, irritability and sleep disturbance arising in the first week postpartum (Grigoriadis et al., 2013b). Critically, these symptoms emerge when breastfeeding is first being initiated and, coincidentally, when women may be suffering from the blues. This confluence of events may contribute to attachment difficulties for the new mother.

Second, it has recently been reported that infants who have been exposed to SSRIs during pregnancy, have an increased risk of having a low Apgar score at 5 minutes (Jensen et al., 2013); this is a risk factor for poor intellectual performance in adolescence (Odd et al., 2008).

Finally, SSRIs themselves can have an effect on the course of the pregnancy, with one study finding an increased risk of gestational hypertension (Toh et al., 2009) and pre-eclampsia among women taking SSRIs during pregnancy.

The second issue relates to the nature of depression in pregnancy – if indeed all the depressive-like symptoms seen in pregnancy are in fact due to a major depression. Such symptoms may arise as a consequence of being pregnant, with a misattribution of symptoms. Such symptoms may also arise as a consequence of the poor sleep associated with pregnancy.

When assessing depressive symptoms in pregnancy, care needs to be taken to ensure the symptoms are not the result of other factors, such as discontinuation syndrome (if antidepressants have been withdrawn), sleep disturbance, or physical complaints associated with the pregnancy. Such symptoms also need to be assessed carefully, and not just cross-sectionally, as some depressive-like symptoms may be transient expressions of distress and do not require treatment.

The final issue is the severity of the depression, as many women may be experiencing mild to moderate depression. There is increasing evidence about the low efficacy of SSRIs in mild to moderate depression, with little difference seen between drug and placebo in clinical trials (Barbui et al., 2011). It needs to be emphasised that pregnant women are routinely excluded from clinical trials. Non-pharmacological treatments may be more appropriate for depression in pregnancy.

So what should a clinician conclude from these observations? There are two take-home messages. First, while there is a small, but acceptable increased risk of congenital abnormalities following exposure to SSRIs, there are other risks to be taken into account. Given this, I would argue that caution is still warranted in prescribing antidepressant medication during pregnancy, especially when there are alternative, effective and safe non-pharmacological treatments that can be applied for depression in pregnancy. If there are clear indications that pharmacotherapy is necessary (such as for moderate to severe depression or disabling anxiety), then it should be used ideally at the lowest effective dose.

Second, we should always be mindful of the risks associated with antidepressants when prescribing them to any woman of childbearing age. Women should be informed about these risks at the initiation of treatment and their treatment reviewed if they want to conceive. If this is not under consideration, then having a discussion about contraception is important.