Another reason to hate the flu: bipolar disorder

tumblr_mh6nxjOh1I1rog5d1o1_400As if pregnant women don’t have enough to worry about! An interesting paper by a group I used to work with just came out in JAMA Psychiatry: Gestational Influenza and Bipolar Disorder in Adult Offspring. The authors report that children born to mothers who caught the flu during pregnancy have an almost four-fold risk of developing bipolar disorder.

The idea that suffering from an infection during pregnancy predisposes your child to develop psychiatric disorders isn’t a new one. A group that includes a lot of researchers at Columbia University and Kaiser Permanente has been working in this area for a long time. In the past, most of their research has focused on schizophrenia. For decades, people had been bandying about theories on the prenatal environment and schizophrenia (I discuss some of them in this book chapter, in case you are interested). There is a well known finding that birth month affects schizophrenia risk, for example. People born in winter/early spring are more likely to develop the disorder. Scientists and doctors had hypothesized that low vitamin levels or exposure to influenza during a particularly vulnerable period of gestation could explain this link–but without a good dataset, it was hard to get a good feel for the processes at work. Imagine the problem from a scientist’s perspective: somehow, you have to reliably link what happened during pregnancy with mental health outcomes decades later. In the United States, our healthcare system is so fragmented that it’s really tough to do this. Let’s say that I’m diagnosed with schizophrenia at my age: 32. What are the odds that a researcher is going to be able to locate my mom’s health records from pregnancy? What are the odds that they even still exist? And then imagine someone trying to do the same for 100 other people like me AND for many more individuals who don’t have schizophrenia, to serve as a comparison group. Not very likely, right? One solution came from a very unique insurance/healthcare company: Kaiser Permanente.

The Prenatal Determinants of Schizophrenia study started with a group of about 12,000 babies born during the years 1959-1967 in the Bay Area, whose mothers were enrolled in the Kaiser Permanente Health Plan. Kaiser still has all the medical records from their mothers’ pregnancies, as well as their records from childhood and beyond. What’s even more incredible is that biological samples from many of the mothers, taken during pregnancy, are available to test for various things (like antibodies to influenza). The same goes for blood samples from the fathers and, in some cases, even cord blood samples. You can imagine that this sort of setup is a treasure trove for researchers. Decades after these people were born, investigators were able to identify the individuals who had developed schizophrenia. Then, by comparing the prenatal conditions encountered by people with schizophrenia to those experienced by individuals from the same group without the disorder, they could learn more about which factors appeared to increase risk.  This study has yielded all sorts of fascinating findings. When I was working with this group, I found that higher maternal levels of the n-3 fatty acid DHA, which is important in fetal and infant brain development, were linked to an increased risk of schizophrenia in offspring. It’s not clear why this would be–maybe higher levels of DHA indicate that a woman ate more seafood, which could contain mercury or toxins bad for a baby. The data on maternal infections collected in this project are much clearer, though: influenza, toxoplasmosis, respiratory infections, and genital/reproductive tract infections have all been linked to a higher risk of schizophrenia in offspring.

How general are these results? Do prenatal infections also increase the risk for other psychiatric disorders? Or are there different prenatal risk factors for each psychiatric disorder? Recently, Alan Brown (Columbia University) and colleagues have been developing a new study on the prenatal determinants of bipolar disorder, also using the Kaiser Permanente cohort, to get at these very questions. They have identified almost 100 individuals diagnosed with bipolar disorder (their “cases”) whom they can compare to “controls”–people who were also born into the Kaiser Permanente system but didn’t develop bipolar disorder. By combing through old medical records, these investigators were able to identify about 30 mothers who had been diagnosed with influenza during pregnancy. They could then determine if babies born to mothers who had the flu were more likely to develop bipolar disorder. And because they have a wealth of information about the families enrolled in the healthplan, they were able to control for important factors such as socioeconomic status, how old the mother was, whether the mother had been diagnosed with bipolar disorder, etc. This study was particularly exciting because the finding was relatively strong. A lot of times in public health, some risk factor appears to increase the risk of developing a disease by 20% or so. When that happens, you worry that the finding could be spurious–maybe some factor is acting as a confounder and you were unable to completely remove its effect. Here, the results are pretty dramatic. These babies were FOUR times more likely to develop bipolar disorder, and the statistical difference in risk between them and people who were not exposed to the flu during gestation was very significant. I expect we will see this finding replicated in other studies in the future.

As the research progresses, I’m curious to see how the prenatal risk factors for diseases such as schizophrenia and bipolar differ–if they differ. The same genetic profile can predispose people to multiple psychiatric disorders, like schizophrenia, bipolar, and depression. Exposure to famine during pregnancy has been linked to both schizophrenia and bipolar in offspring. At this point, prenatal influenza infection has also been linked to both schizophrenia and bipolar disorder. Are we likely to find any prenatal risk factors that are specific for a psychiatric disorder like bipolar?

One of the things I like about this vein of research is that if these findings are replicated, and we all agree that getting the flu during pregnancy puts your baby at risk for bipolar disorder, there is an easy solution. We know that getting the flu during pregnancy is bad for the mother and baby for a whole host of additional reasons, so it’s already recommended that pregnant women get the flu shot. For those who worry that the vaccine might be dangerous for the fetus or that the shot may not be effective enough to be worthwhile, take heart! This year a paper published in the New England Journal of Medicine showed that getting the vaccine reduced the risk of getting the flu by roughly 70% in pregnant women and that the vaccination posed no threat to the fetus (and may actually have prevented fetal deaths). Many risk factors for psychiatric disorders are not easily changed, but this doesn’t appear to be one of those cases. It’s one of those rare public health stories that could have a happy ending!

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