By Dr. Adam Urato
On Friday, a new study was released in the British Medical Journal showing that antidepressant use during pregnancy is associated with autism in the exposed children. This is now the second study within the last two years showing this link and it adds to the accumulating evidence of potential harm associated with the use of antidepressants during pregnancy.The study was a case-control study from Sweden, which was fairly large: it looked at 4,429 cases of autism spectrum disorder and compared these cases to 43,277 matched controls. The researchers found that antidepressant use during pregnancy, with either SSRIs or nonselective monoamine reuptake inhibitors (another type of antidepressant) was associated with an increased rate of autism spectrum disorders in the offspring. The odds ratio was high at 3.34, which roughly means that antidepressant use was associated with more than a tripling of risk of autism in the children.
The study concludes:
In utero exposure to both SSRIs and non-selective monoamine reuptake inhibitors (tricyclic antidepressants) was associated with an increased risk of autism spectrum disorders, particularly without intellectual disability. Whether this association is causal or reflects the risk of autism with severe depression during pregnancy requires further research. However, assuming causality, antidepressant use during pregnancy is unlikely to have contributed significantly towards the dramatic increase in observed prevalence of autism spectrum disorders as it explained less than 1% of cases.
These results do not surprise those of us who have been following the scientific studies in this area over the past two decades.
Serotonin: a crucial neurotransmitter
Serotonin, the first neurotransmitter expressed in the developing embryo, plays a crucial role in brain formation. Serotonin is essential for the growth and development of certain areas of the brain. It is involved in such basic processes as cell division, differentiation, migration and synaptogenesis. In short, proper functioning of the serotonin system is essential for the brain to form and function normally. The SSRIs and other such antidepressants are believed to exert their effects by blocking the reuptake of serotonin into neurons—the basic cell of the brain. For a developing baby, such blockade is occurring throughout the body (including the brain) and throughout pregnancy development. It is now well-established scientifically that autism is characterized by changes in the serotonin system. Hyperserotonemia is the most consistent neurochemical change in autism.
Most of the data we have on developmental effects of the SSRIs on the brain comes from animal studies on small mammals (mice and rats). The majority of these studies show significant changes in the brains and behavior of exposed animals and these results are very concerning. The two best-known studies were published in the world’s leading scientific journals, Science (2004) and in the Proceedings of the National Academy of Sciences (PNAS) (2011). But these are just two examples of the many animal studies that show changes in the brain and behavior that result when the serotonin system is altered during development by the use of the SSRI antidepressants. In the Discussion section of these manuscripts, again and again, the authors warn us that their findings of harmful effects should make us concerned with using them in humans.
Several human studies looking at the effects of SSRI exposure during pregnancy have shown brain and behavioral changes in exposed children. In 2009, Pawluski, et al published a landmark study showing decreased S100B protein levels in babies who were exposed to SSRIs in utero—similar to alcohol and cocaine-exposed pregnancies. In 2010, Pedersen, et al demonstrated that SSRI-exposed children sat up and walked later and that they had behavioral changes. In 2011, Bellisima, et al showed that babies exposed to SSRI antidepressants in utero have dramatically higher levels of the brain damage marker Activin A in their blood and amniotic fluid. In 2013 Hanley, et al showed that SSRI-exposed children scored lower on gross motor and social-emotional testing. And these are just four of many studies that show changes in exposed children.
As far as autism goes, the first study came out in 2011. Croen, et al showed that SSRI exposure during pregnancy was associated with a doubling of the risk of autism. For first trimester SSRI exposure, the risk was almost quadrupled. Importantly, her study looked at depressed women not on SSRIs, and in this group there was no increased risk of autism. It was the antidepressant use that was linked to the autism and not the depression.
The current study by Rai, just published April 19th , also shows an increased rate of autism in antidepressant-exposed children and this does not appear to be a result of depression, but rather of the medication. Thus, the only two studies in humans that have asked the question: “Is antidepressant use during pregnancy associated with autism?” have found the answer to be a clear “Yes.”
The authors of the recent study concluded that they cannot declare whether the problem is with the antidepressants or the depression. Many readers find this confusing. The reason the authors state this is that their study was not a randomized controlled trial (RCT). Only a randomized controlled trial (where half the depressed women are given an antidepressant and the other half a placebo) can most accurately assess causation. However, this type of trial has never been done with antidepressants during pregnancy and many people feel that such a trial would not be ethical.
However, an RCT is not always needed to presume that an agent is causing harm (for example, we have never had an RCT on cigarettes, but we have concluded that they cause harm) and an RCT is not needed to caution the public. In this case, we see clearly from the animal studies that exposure to SSRIs during development leads to changes in the brain and behavior –that often mimic the findings in autism. Then, in the only 2 human studies to look at this area, we see increased rates of autism in the antidepressant exposed groups (and not in the depressed/nonmedicated group.)
Balancing Risks and Benefits
SSRI antidepressant use during pregnancy is linked to pregnancy complications and risks for the baby, including what may be an increased risk of autism. These complications might be considered tolerable if there was solid evidence of benefit with the use of antidepressants by pregnant women. Sadly, in 25 years of study, not a single study has ever shown improvements in pregnancy outcomes in the antidepressant-treated group. In studies of nonpregnant populations, there is little evidence of clinically significant benefit with the use of antidepressants (when compared with placebo) by most patients with depression.
This second study showing an increased risk of autism in the children who were exposed to antidepressants during pregnancy is concerning. The current evidence that the SSRI antidepressants can injure the developing brain is clear and consistent. Pregnant women suffering from depression need treatment and care. But, with good evidence that non-drug therapies, such as psychotherapy and exercise, may provide at least as much benefit in the treatment of depression (if not more), it makes sense to first use these approaches in women of childbearing age—approaches that have not been linked to autism.
Adam C. Urato, MD is a maternal-fetal medicine physician at Tufts Medical Center, Assistant Professor of Obstetrics & Gynecology at Tufts University School of Medicine and Chairman, Department of Obstetrics & Gynecology, MetroWest Medical Center in Framingham. He has written previously on this topic here.
For another perspective, see this piece by a psychiatrist specializing in women’s mental health issues.