Antidepressants, pregnancy, and autism: the real story

For the video version of this post, click here.

If you're a researcher trying to grab some headlines, pick any two of the following concepts and do a study that links them: depression, autism, pregnancy, Mediterranean diet, coffee-drinking, or vaccines.  While I have yet to see a study tying all of the big 6 together, waves were made when a study appearing in JAMA pediatrics linked antidepressant use during pregnancy to autism in children.

To say the study, which trumpets an 87% increased risk of autism associated with antidepressant use, made a splash would be an understatement:

The Huffington post wrote:

The Daily telegraph, rounding up, said:

Newsweek:

But if you're like me you want the details. And trust me, those details do not make a compelling case to go flushing all your fluoxetine if you catch my drift.

Researchers used administrative data from Quebec, Canada to identify around 145,000 Singleton births between 1998 and 2009. In around 3% of the births, the moms had been taking anti-depressants during at least a bit of the pregnancy. Of those kids, just over 1000 would be diagnosed with autism spectrum disorder in the first 6 years of life. But if you break it down by whether or not their mothers took antidepressants, you find that the rate of diagnosis was 1% in the antidepressant group compared to 0.7% in the non-antidepressant group. This unadjusted difference was just under the threshold of statistical significance by my calculation, at a p-value of 0.04.

These numbers aren't particularly overwhelming.  How do the researchers get to that 87% increased risk? Well, they focus on those kids who were only exposed in the second and third trimester, where the rate of autism climbs up to 1.2%.  It's not clear to me that this analysis was pre-specified. In fact, a prior study found that the risk of autism increases only when antidepressants are taken in the first trimester:

And I should point out that, again by my math, the 1.2% rate seen in those exposed during the 2^nd and 3^rd trimesters is not statistically different from the 1% rate seen in kids exposed in the first trimester. So focusing on the 2^nd and 3^rd trimester feels a bit like cherry picking.

And, as others have pointed out, that 87% is a relative increase in risk. The absolute change in risk remains quite small. If we believe the relationship as advertised, you'd need to treat about 200 women with antidepressants before you saw one extra case of autism.

But I'm not sure we should believe the relationship as advertised. Multiple factors may lead to antidepressant use and an increased risk of autism. Genetic factors, for example, were not controlled for, and some studies suggest that genes involved in depression may also be associated with autism. Other factors that weren't controlled for: smoking, BMI, paternal age, access to doctors. That last one is a biggie, in fact. Women who are taking any chronic medication likely have more interaction with the health care system. It seems fairly clear that your chances of getting an autism diagnosis increase with the more doctors you see. In fact, in a subanalysis which only looked at autism diagnoses that were confirmed by a neuropsychologist, the association with antidepressant use was no longer significant.

But there's a bigger issue, folks – when you take care of a pregnant woman, you have two patients. Trumpeting an 87% increased risk of autism based on un-compelling data will lead women to stop taking their antidepressants during pregnancy. And that may mean these women don't take as good care of themselves or their baby. In other words, more harm than good.

Could antidepressants increase the risk of autism? It's not impossible. But this study doesn't show us that. And because of the highly charged subject matter, responsible scientists, journalists, and physicians should be very clear. Women taking anti-depressants during pregnancy, do not stop until, at the very least, you have had a long discussion about the risks with your doctor.

Combining these two common medications might kill you.

For the video version of this post, click here. With depression a major health problem, and broadening indications for antidepressants, these medications are seeing rapidly increasing use.  Non-steroidal anti-inflammatory drugs (NSAIDs), ranging from indomethacin, to ibuprofen, to the cox-2 inhibitors, are also very frequently used. Simple logic would tell us that there would be significant overlap in the Venn diagrams for these two classes, but it turns out that individuals with depression are more likely to experience chronic pain, and thus, more likely to take NSAIDs. The combination of these two classes may be problematic.

The problem is that the most commonly used class of antidepressants, the SSRIs, may increase bleeding risk by reducing serotonin uptake by platelets. And NSAIDs can mess with platelet function in multiple ways.  Now a study by Korean researchers, appearing in the BMJ suggests that the concomitant use of both of these agents can significantly increase the risk of intracranial hemorrhage.

This was a large, population-based study using the Korean national medical database. The researchers looked for everyone with an incident antidepressant prescription from 2009 to 2013.  Of these roughly 5 million individuals, just about half had received an NSAID prescription within the 30 days following the antidepressant. That proportion seems crazy to me, but apparently you can’t get NSAIDs over the counter in Korea, so the demand for prescriptions must be high.

Rather than comparing the NSAID group to the no NSAID group directly, the researchers matched NSAID users with non-NSAID users with similar qualities using propensity scores - this left roughly 2 million people in each group for analysis.

The results? Well, the intracerebral hemorrhage rate was about 60% higher in the group taking NSAIDs.  Now, the overall risk was low - you’d need to prevent around 250 people from taking NSAIDs to prevent one intracerebral hemorrhage, but there are a few issues with the study that make me question the results.

First - an issue of interpretation.  The authors state that caution should be used when combining NSAIDs with antidepressants.  But they don’t have data on people who take neither drug, nor do they have data on people taking NSAIDs alone. So the picture is incomplete.  Maybe NSAIDS increase the risk of intracerebral hemorrhage and antidepressants have nothing to do with it.

We also saw no difference based on the type of antidepressant prescribed. SSRIs, due to their mechanism of action, should increase bleeding risk more than tricyclics for example, but we don’t see that here.

Finally, the follow-up period was only 30 days, and the median length of follow-up was only 14 days. While a signal seen in such a short period of time may be compelling, it doesn’t help us advise our patients who are using antidepressants for a longer period of time.  This is a potential interaction worth following up on in more robust studies, but until we know more, I suggest we continue to do our best to relieve all types of pain.