How to Interpret Research on Acetaminophen During Pregnancy

I want to take a minute to talk about the potential link between acetaminophen use during pregnancy and the potential risk of having a child with autism spectrum disorder. I did a post about this a few days ago. It got a lot of attention. This is something that I've been a little concerned about for the last 10 years. I've posted about it on social media for the last 10 years. I've talked about it on podcasts, and I never got the response that I did a few days ago.

This is an association. This is not something that has been established as causation. There are studies for and against this association. Many studies have supported the potential link between acetaminophen use during pregnancy and the risk of having a child with autism spectrum disorder. From those studies, it seems as though women who use acetaminophen during pregnancy have a higher risk of having a child with either autism spectrum disorder, ADHD, or behavioral, verbal, or motor delay if they have a child who is male but not female. In other words, it seems as though females are not as vulnerable to this environmental stress, in this case acetaminophen use. There have been meta-analyses showing this association.

However, there was recently a large cohort study out of Sweden. It included about 2.5 million participants and was published in JAMA. It also found an association between acetaminophen use during pregnancy, as documented from prescriptions, and the risk of having a child with autism spectrum disorder. Women who were prescribed acetaminophen were considered to be using acetaminophen. However, that risk disappeared when sibling analysis was applied.

I do want to point out that even though this one study was large and used sibling analysis, it doesn't mean that there isn't a potential association between acetaminophen use during pregnancy and the risk of having a child with autism spectrum disorder. There are a lot of things that we don't know that are potentially going on. For one, I just mentioned that multiple studies have found the link between acetaminophen use during pregnancy is much stronger for males than females, in other words, if you have a boy versus a girl. The sibling analysis did not stratify the data according to sex. In other words, the effect in females could dilute the positive association seen in males. That's something to consider. I'm not saying that's the only thing making this association disappear after this type of analysis. I'm saying it is one thing to consider. Yes, there are probably other familial factors contributing as well. But the fact of the matter is that multiple studies have found this association.

Probably one of the strongest datasets that I've seen is an actual biochemical analysis. Cord-blood acetaminophen levels were measured, and the offspring were assessed for whether the child was diagnosed with autism spectrum disorder. That study found a dose-dependent effect. In other words, the higher the levels of acetaminophen in cord blood, the stronger the risk of having a child with autism spectrum disorder was. Mothers in the highest tertile of acetaminophen levels in their cord blood had a 3.6-fold higher risk of having a child with autism spectrum disorder compared with people in the lowest tertile.

That's pretty strong evidence. One, because it's dose-dependent. Two, because it's actual biochemical data. We're not just looking at a prescription. We're not just relying on a questionnaire asking a mother to think back about whether she used acetaminophen. Not to mention, that study also found that 100 percent of the measured samples had acetaminophen levels. In other words, even women reporting that they don't use acetaminophen may not actually remember using it. That's also something to keep in mind when we're talking about these studies and the conflicting data.

We also have preclinical data showing plausible mechanisms. There are multiple mechanisms. I'm not going to talk about them all right now. I want to save that for a long-form podcast. But we know that boys are more vulnerable to this type of environmental stress, and it's not just acetaminophen. It's other types of environmental stress as well, such as BPA and plastic chemicals. It seems as though there's a vulnerability there. With acetaminophen, one proposed mechanism is that it's interfering with aromatase signaling during brain development. We know that is very important for brain development, and that has been associated with an increased risk of autism spectrum disorder.

All this said, I don't think acetaminophen is the single cause of autism. Absolutely not. There are so many different contributing factors. Genetics is a big one, as are epigenetics and maternal infection. Maternal infections are associated with an increased risk of autism spectrum disorder. Other factors include immune dysregulation, autoimmunity, and vitamin D deficiency. I've published two studies on vitamin D deficiency being linked to increased risk of autism spectrum disorders, as well as other environmental insults such as the plastic chemicals I mentioned. Air pollution is another one. The list goes on and on.

All this is to say that there are a lot of contributing factors and probably a lot of gene-environment interactions that we don't quite understand. The point is not that we need to make women scared of taking Tylenol during pregnancy. The point is that there needs to be a conversation with pregnant women, letting them know and informing them that there could be a potential association with repeated use of acetaminophen during pregnancy. We don't quite understand this association. It's potentially there. I think that conversation needs to be had because it might influence the way a woman uses Tylenol during pregnancy.

In other words, it may change a woman's use from weekly use for any minor ache or pain to perhaps using it as a last resort if she has a fever. That's the kind of context in which you'd want to use a fever-reducing medication that is at least probably the safest to use during pregnancy.

I'm trying to get the point across that I think this association needs to be discussed more. It's not a closed book. Just because one or two sibling-analysis studies have made that association disappear doesn't mean it's not a real association. It means we don't understand what's going on and need to continue having conversations around it.

At the end of the day, as I said, I've posted about this before. I've been interested in it for the past 10 years and never received this response. I think people responded negatively because it has become a political issue. It really should not be a red or blue issue. It should be an issue of trying to understand all these potential contributing factors to autism spectrum disorder. What are the potential interactions between genes and the environment? Is there a dose-dependent effect? Maybe it's the women who are taking acetaminophen on a weekly basis. We need to understand all these questions. We need to keep talking about them and not make this a political issue. Anyway, thanks for listening.