Editorial Note: This post by Adam Urato from Boston picks up one of the most important issues of our time. It touches on one of the most sensitive issues of all – should anyone tell a mother-to-be what to do about medications like the Antidepressants. See The Dark is for Mushrooms.
Does antidepressant use during pregnancy lead to autism in the exposed children? This is a very important question, which new research is beginning to address—and the findings are concerning.
Prozac, the first of the SSRI (selective serotonin reuptake inhibitor) antidepressants, was launched in 1987 and sales have risen since then. Women of childbearing age make up a large percentage of SSRI users. Estimates are that up to 13% of US pregnancies are exposed (or around 500,000 US pregnancies per year.) How the SSRIs affect pregnancy has been an area of increasing concern. Current evidence suggests that antidepressant use during pregnancy is associated with miscarriage, birth defects, preterm birth, and newborn behavioral syndrome along with other pregnancy complications such as preeclampsia and low birth weight. The SSRIs appear to be associated with pregnancy complications, but a major area of concern is what the effects are on the developing brain of embryos and fetuses exposed to these drugs. Available scientific data from animal and human studies raise serious concerns that exposure to SSRIs during pregnancy damages the developing brain and may cause neurodevelopmental abnormalities—including autism.
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 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.
Animal studies are concerning
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 some of 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.
Human studies are also finding problems
Several human studies looking at the effects of SSRI exposure during pregnancy have shown brain and behavioral changes in exposed children. In 2003 Casper, et al showed that SSRI exposure during pregnancy had effects on motor development in young children. In 2009, Pawluski, et al published a landmark study showing decreased S100B protein levels in babies who were exposed to SSRIs in utero—decreased S100B protein levels being the same as what we see in 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 five of many studies that show changes in exposed children.
As far as autism, 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 second study on the topic by Rai, et al was published in April, 2013 and also showed an increased rate of autism in antidepressant-exposed children and that this did not appear to be a result of depression but rather of the medication.
The third study (by Sorensen) and fourth study (by Hviid) are both from Denmark and both use basically the same database. Both of these Danish studies found that children who were exposed prenatally to antidepressants had an increased risk of autism spectrum disorder compared with unexposed children. However, in these studies, after statistical correction was employed, increased risk was not found to be statistically significant. But there are a few issues that need to be understood about these Danish studies.
First, rates of antidepressant use during pregnancy in Denmark are very low. While studies in the US show rates of 5%, 10%, or close to 15% in some subgroups, the rate in Denmark is around 1%. Second, these Danish studies are based on the same large registry and we know that registry studies most often tend to underestimate risk. Registries are large collections of data—in the case of Denmark there were more than 600,000 patients studied. In large registries it is hard to be certain who actually is taking medications and the result is to underestimate risks. Finally, in the Danish registry we do see an association between SSRI antidepressant use and child autism but the authors state that the result is not statistically significant. What this means statistically is that the authors cannot say that an association exists with 95% certainty. But for most patients and the public, 95% certainty is not necessary to cause concern.
Thus, we are seeing clearly concerning signals in the four human studies that have asked the question: “Is antidepressant use during pregnancy associated with autism?”
Risks worse than we thought
In late 2013, an important new study came out in the Journal of Clinical Epidemiology. In this study, a group of researchers from Norway asked a simple question: “Are the women who are getting prescriptions for SSRIs prior to pregnancy actually taking the medications during pregnancy?” This is a crucial question because many of the studies on the topic of SSRIs and pregnancy make the assumption that women who are given a prescription for an SSRI in the months before pregnancy should be classified as “users” of the drug during pregnancy. The researchers from Norway, however, showed that many of these women are not using the drugs during the pregnancy. And when the studies are done and they include these women as users it makes the SSRIs look much less risky than they really are. What this means is that many of these studies showing that SSRI use in pregnancy leads to complications (for example, miscarriage, birth defects, preterm birth, newborn complications, etc.) are actually underestimating the risk: SSRI use in pregnancy is actually even riskier than we had thought.
Putting it all together
A developing embryo and fetus has millions of serotonin receptors and serotonin plays a critical role in development. Why wouldn’t chemically interfering with this system affect human development—particularly in the brain? The SSRI antidepressants have been shown to be linked to miscarriage, preterm birth, and other pregnancy complications that suggest that the drugs can cause injury to the developing baby/pregnancy. It should come, then, as no surprise that such medications could injure the fetal brain.
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.
The current evidence that the SSRI antidepressants can injure the developing fetal 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 pregnancy complications or outcomes such as autism.