A woman who is depressed in pregnancy faces the difficult process of weighting the pros and cons of starting antidepressant treatment, but unfortunately the evidence regarding the effects of antidepressants in pregnancy on offspring outcomes remains far from conclusive. At the same time, more studies are showing that untreated depression per se has negative consequences on offspring outcomes. Weighing the pros and cons in this context is by no means an easy process.

A number of population-based studies using prescriptions registers have found that treatment with antidepressants in pregnancy, especially with selective serotonin reuptake inhibitors, is associated with an increased risk of cardiac malformations (for exposure in the first trimester) and of pulmonary hypertension in the newborn (for exposure in the third trimester) (Pedersen et al, 2009; Grigoriadis et al, 2014). However, there is one main caveat: it is very difficult to distinguish the effects of antidepressants from the effects of untreated depression, as prescriptions registers often lack clinical information, and treatment allocation is not randomized. Even comparing the naturalistic cohorts of treated and untreated depressed women cannot adjust for the fact that treated women are likely to be more complex and more severely depressed—and therefore more likely to smoke, to drink alcohol, and to have less regular antenatal care. Indeed, one very recent study that has attempted to adjust for such variables using the US Medicaid database has found no substantial increase in the risk of cardiac malformations attributable to antidepressants (Huybrechts et al, 2014). Even the (small) increase in pulmonary hypertension attributable to antidepressants could be explained by the higher risk of prematurity described in women who are depressed (Grigoriadis et al, 2014).

In the face of this recent, reassuring evidence about antidepressants’ use in pregnancy, longitudinal studies are confirming the long-lasting adverse consequences of untreated depression in pregnancy for the emotional development of the offspring, and especially the increased risk of the offspring being exposed to maltreatment and bullying in childhood, and developing depression and antisocial behavior in adolescence and early adulthood (Pawlby et al, 2011; Pearson et al, 2013). These effects seem to be specific to depression during pregnancy, as they are not explained by the fact that these mothers tend to be depressed also postnatally: they thus implicate in utero ‘biological programming’ as one of the potential mechanisms. Indeed, stress and depression in pregnancy can affect the placental expression of enzymes regulating cortisol levels as well as offspring’s stress response, methylation status of stress-related genes, and volume of the amygdala (Buss et al, 2012). Future studies should dissect the interaction between this complex constellation of factors, including depression in pregnancy (and its biological correlates, such as maternal cortisol and inflammation levels), infant stress-related behavior (again, with its biological correlates), mother–infant interaction, mother attachment, and offspring temperament.

Where do these studies leave the patients and the professionals? While starting an antidepressant in pregnancy may be perceived as ‘an action’, carrying moral responsibility (and liability), the alternative ‘no action’ of leaving a depressed woman untreated may harm the offspring through exposure to toxic life styles and an abnormal in utero biology. While non-pharmacological treatments may work in these women (for example, interpersonal psychotherapy, exercise, or omega-3 fatty acids), antidepressants will likely remain the mainstream option for moderate to severe depression in pregnancy (unless electroconvulsive therapy is required, a safe option in the most difficult cases). ‘Not to treat’ is no longer the safest choice.

FUNDING AND DISCLOSURE

Professor Pariante is funded by the National Institute of Health Research (NIHR) Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and at King’s College London (London, UK). Professor Pariante has received research funding from pharmaceutical companies interested in the development of antidepressants, but there is no conflict of interest in connection with the topic of this article.