Pregnancy, Multiple Sclerosis, and Vitamin D: The Latest Hype

A study appearing in JAMA neurology links better Vitamin D level in pregnant women to a lower risk of multiple sclerosis in their offspring. There are some really impressive features of this study, but there are some equally impressive logical leaps that seem to defy the force of epidemiologic gravity. Let's give  the study some sunlight.

For the video version of this post, click here.

The study was run out of Finland, which is a country that figured it might be a good idea to keep track of the health of its citizens. In fact, since 1983, nearly every pregnant woman in Finland has been registered, and a blood sample sent to a deep freezer in a national biobank. The researchers identified 193 individuals with MS, and went back into that biobank to measure their moms' vitamin D levels during pregnancy. They did the same thing with 326 controls who were matched on their date of birth, mother's age, and region of Finland.

This is from the first line of their discussion:

Wow. 90%. That sounds scary. And the news outlets seem to think it is scary too.  But that impressive result hides a lot of statistical skullduggery.

Here's the thing, Vitamin D level is what we call a continuous variable. Your level can be 5, 10, 17, 42, whatever – any number within a typical range. When you study a continuous variable, you have to make some decisions. Should you chop up the variable into categories that others have defined (like deficient, insufficient, normal), or should you chop it up into even-sized groups? Or should you not chop it up at all?

As a general rule, you have the most power to see an effect when you don't chop at all. Breaking a continuous variable into groups loses information.

When the Vitamin D level was treated as the continuous variable it is, there was no significant relationship between Vitamin D level in mom and MS in the child. When the researchers chopped it into 5 groups, no group showed a significantly higher risk of MS compared to the group with the highest level. Only when they chopped the data into 3 groups did they find that mom's who were vitamin D deficient had 1.9 times the risk of those that were insufficient. That's the 90% figure, but the confidence interval ran from 20% to 300%.

And did I mention there was no accounting for mothers BMI, smoking, activity level, genetic factors, sun exposure or income in any of these models? Despite that, the paper's conclusion states :

That statement should go right on the jump to conclusions mat.

Look, I'm not hating on Vitamin D. I actually think it's good for you. But research that adds more to the hype and less to the knowledge is most definitely not.

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.