Acetaminophen and ADHD

So I read this article Monday, about a study linking acetaminophen use during pregnancy to ADHD-like behaviors in children. I am mildly irritated by the study itself, and super pissed about a lot the reporting on the study. (Raise your hand if you’re shocked!) Since reading it Monday when Jess brought it to my attention, I’ve seen this article as well as a few others flying around on twitter and facebook, and I’ve heard people express worry, fear, and worst of all, guilt. So I figured it might be valuable to pick it apart, a bit, as well as to broadly discuss the kind of messaging directed at pregnant women, and mothers in general, when studies like this are discussed in the media and elsewhere.

What the study did: The study used several robust and interconnected data sets to look at the correlations of interest. These are actually really cool – in Denmark, there are a few programs that work together to collect a lot of health data on a TON of individuals to facilitate epidemiological studies. (In fact, some of the studies that illustrated pretty definitively that vaccines don’t cause autism came out of these programs!).

  • Danish National Birth Cohort: this program enrolls pregnant women at about 6-12 weeks of gestation (like, when they go to the OB upon becoming pregnant, they are asked if they’d like to participate – and something like 30% of all pregnant women in Denmark do). As part of this study, they complete a telephone interview at 12 and 30 weeks of gestation, and another six months after the birth of the child, as well as a child behavioral questionnaire (Strength and Difficulties Questionnaire, SDQ) at seven years of age. The telephone interviews included questions about use of pain killers, and women were asked to recall specific medications taken on a week-by-week basis for the preceding weeks (i.e., at the 12 week phone call, they were asked to report which medications they took during each of the preceding weeks of their pregnancy). The SDQ was used to identify ADHD-like behaviors.
  • Danish National Hospital Registry and Danish Psychiatric Central Registry: these programs use unique civil identification numbers to track hospital admissions. The researchers tracked diagnoses of Hyperkinetic Disorder (HKD) through these registries.
  • Danish Prescription Registry: this program uses the civil ID numbers to track prescription drug use. The researchers used this to track the use of ADHD drugs (Ritalin*, atomoxetine, and modafinil).

Using these data sets, the researchers stratified and analyzed their data according to various features and/or confounders, such as

  • acetaminophen use profile (how many weeks of use, and during which trimesters/weeks)
  • SDQ scores (<17, or ≥17)
  • HKD diagnosis
  • ADHD medication use
  • Demographic info, like birth year, birth weight, sex, maternal age at birth, parity, gestational age at delivery, socioeconomic status, smoking and alcohol use during pregnancy, maternal BMI, etc.
  • Diseases of conditions that could trigger acetaminophen use, such as muscle and joint disorders, fever, inflammation, or infection (all self-reported).

So, to recap, the exposure of interest is acetaminophen use by week of gestation, and the outcomes of interest are ADHD-like behaviors, HKD diagnosis, and/or ADHD medication use.

What the major findings were:

  • More than 50% of mothers in the study used acetaminophen at least once during their pregnancies. The flip side of this really surprised me – more than 40% of women DIDN’T take even a single solitary Tylenol for nine months? Damn.
  • Compared to the no exposure group, there were increased risks for all outcomes of interest (ADHD-like behavior, KHD diagnosis, and ADHD medication use) in children of mothers who used acetaminophen during pregnancy.
  • For each outcome, the risk was GREATER for children of mothers who used acetaminophen in more than one trimester, or in all three trimesters, or for more than 20 weeks during pregnancy.

Issues I have:

Some of my issues are impossible to solve – you’re never going to get an enormous epidemiological study like this where they can get good, detailed information on the actual DOSE of medication people are taking. You get binary information (did they or didn’t they, over the whole nine months? Did they or didn’t they, on any given week?), rather than something quantitative (how MUCH did they take and when?). That makes it impossible for the researchers to study the critically important dose-response relationship, because they don’t actually have any idea what the dose was for any of these women. These researchers try to get at this relationship by using weeks of use as a kind of surrogate for dose, but it’s kind of messy. They track the number of weeks the mothers used it. They track WHICH weeks the mothers used it. But neither of those is the same as HOW MUCH. And while they make it sound like there is a clear correlation between number of weeks and strength of association, it’s not… THAT clear. The confidence intervals are really wide and overlap a lot with each other, and in many cases, with the non-exposed group. The associations ARE interesting, but they are NOT dramatic.

I’m starting to touch on the language used to discuss risk, here. The study relies on measures of risk called “risk ratios” and “hazard ratios.” What the heck are those? A risk ratio is a measure of RELATIVE risk between two states. So the unexposed group has a risk ratio of 1.0, and serves as a baseline or reference scenario. Then, let’s say an exposed group has a risk ratio of 1.46 with a confidence interval of 1.16 – 1.85 (this is a real example from the paper: the adjusted risk ratio for ADHD-like behaviors for children of mothers who used acetaminophen for more than 20 weeks of their pregnancies). Another way of correctly stating the observed risk for this group would be “the exposed group had a 46% higher rate of ADHD-like behaviors than the unexposed group,” or “the risk of AHDH-like behaviors was increased by 46% relative to the unexposed group.”

Hazard ratios are a little different, and a lot harder to explain, but the interpretation is similar. They are a measure of instantaneous risk over a defined time period. (Now you say: WHAT?) It’s kind of like a risk ratio averaged over time. (WHAT?) Ok, there’s really no easy way for me to explain this, unless you know what person-time is. Maybe you’ve read the insert on your birth control pills before, and it says something about how in a normal year of proper use, 1.7** women in 100 will get pregnant? So, that bit about “in a normal year…” – that’s a person-year. Or, 100 person-years, actually. 100 people, doing the thing of interest, for a year. So it’s the number of outcomes over the total person-years studied, for the exposed group versus the unexposed group. Anyone still here? I swear I just visualized all of my friends backing out of the room slowly.

ANYWAYS. You can talk about hazard ratios in basically the same way as risk ratios. So, for example, the study found an adjusted hazard ratio of 1.53 (1.21 – 1.94) for use of ADHD meds for children of mothers who used acetaminophen (can we abbreviate that shit? Damn. COMWUA? Ack.) for more than 20 weeks of their pregnancies. So we can say “the exposed group had a 53% higher rate of using ADHD meds than the reference group.”

All right, so raise your hand if you’re like, “OMG, FIFTY THREE PERCENT AHHHH” and between this and that This American Life episode, you’re chucking out the only damn drug you were comfortable taking when you were pregnant, because WHOA that’s a lot?

That means it’s time to bring up ABSOLUTE risk. Absolute risk is a measure of the actual incidence of the outcome of interest in a population. So, in this study population, the absolute risk of a child having ADHD-like behaviors despite their moms never taking Tylenol ever was 2.6% (458 hyper kids / 17730 unmedicated moms = 0.0258). The absolute risk for the poor suckers whose moms popped acetaminophen for more than 20 weeks of their pregnancies was…. 3.8%.

When you start layering percentages like this, things get muddy real fast. “46% higher” sounds a heck of a lot scarier than the absolute risk numbers do, to me. And this is where I start to get bent out of shape (1400 words in! We made it!). I think it is appalling, based on this study, for researchers, clinicians, and reporters to make statements like:

“If these results reflect causal associations, acetaminophen should no longer be considered a safe drug for use in pregnancy.” – study authors

“(Pregnant women) shouldn’t worry at this point,” says study author Dr. Beate Ritz, professor and chair of the epidemiology department at the University of California, Los Angeles Fielding School of Public Health. “But if I were a woman who was pregnant … I would try to avoid taking painkillers as much as I can until we know more about this.” – CNN article

“If there is a pregnant woman out there willing to take Tylenol after reading this research — or just the associated headlines — I’d be surprised.” – Motherlode blog, NYTimes

“There are nonpharmacological ways to deal with pain,” says Dr. Jeffrey Chapa, head of maternal-fetal medicine at Cleveland Clinic Children’s Hospital. Massages, baths and acupuncture are some alternatives he suggests to help relieve pain. “I think we have to focus a little bit more on that as opposed to just medications.” – CNN article

I would say the majority of my issues here are with science reporting, as opposed to the research itself. I do think the authors over-interpreted their results a bit – I don’t think that the researchers should be making, or even suggesting making a broad value judgment about whether acetaminophen should or shouldn’t be acceptable for use in pregnancy. I understand why they did – as scientists, we aren’t taught how to write in a fair and balanced way – we are taught to describe our findings and their importance, and then our continuing employment depends on politicians grading that importance. So you end up with inflated statements and sweeping judgments. I get that. I wish it weren’t the case. But at least it isn’t free standing.

My bigger beef, though, is with science reporting – some of it is link bait bull shit – “you’ll never guess what common medication will ruin your kid’s life!” – but even leaving the really egregious examples aside, the tone is just awful. One liners stripped apart from the caveats and quantitative information provided in the original research. And usually science reporting focuses on a single study at a time, rather than the body of literature on that topic, thereby further isolating these often grandiose “findings” from their proper context.

So it ends up as another one liner in the broader conversation about pregnancy, and pregnant women, and what they can and cannot do.

Like, as a pregnant woman, it your JOB to have a neurotypical, model-perfect child, and any deviation from that ideal is a) problematic and b) your fault. That is a seriously dangerous message! And it is everywhere. And for this particular example, well… Some of us actually have these “ailments,” or kids with them. And I know *I* don’t feel like damaged goods over here. Nor do I appreciate the implication that I should.

As this post discusses, there is a catch-22 about use of even common medicines in pregnancy – they aren’t studied in pregnant women because of possible risk to the fetus, so we never have enough information to know if they might be harmful to the fetus, and on and on. So all the meds, and pharmacists, and doctors say: take it if the risks are worth it to you. Which is terrifying language! What are the risks, both of taking the medicine, or of choosing not to? (They never actually TELL me the risks, when I have asked, that is for sure.) How do we weigh those risks in a useful way? There is really very little useful information or discussion to help women navigate these questions. (Sidebar: one of the MOST useful tools for this that I have found – for lay people! – is Motherisk. Or Jen and her handy book.)

The prevailing attitude seems to have evolved to the point that a pregnant woman is viewed as a host, or a vessel, and her mental health and happiness are totally secondary for the duration of pregnancy. I was talking to some friends about this, and one raised a really interesting point – because society has moved towards having fewer children per capita, this attitude has become more and more prevalent. When it was (and in communities where it still is) really common for a woman to have a lot of pregnancies, no one expects a woman to suspend her normal life just because she is pregnant. If you expect to be pregnant or nursing for the better part of a decade (or longer!), it would be preposterous to suggest that you not eat a normal diet, exercise, or engage in normal activities, TREAT PAIN! for that long. I mean, truly absurd.

There is also the point that this particular study treated acetaminophen exposure in kind of a binary way – the null group was totally unexposed. Considering acetaminophen is one of the only drugs that is touted as truly safe for pregnancy, I find it actually kind of hard to believe a woman who didn’t take even one measly tylenol for nine months should be the definition of “baseline.” While they controlled/adjusted their estimates of risk based on things like maternal fever, inflammation, infection, or chronic pain, I would still argue that there is likely a connection between a woman who takes not even a single dose of acetaminophen and someone who might be less willing to seek a pharmaceutical solution for their child’s ADHD-like behaviors.

Additionally, and more importantly, there is evidence suggesting that NOT treating maternal  pain, inflammation, infection – the issues that generally cause people to take acetaminophen – ALSO seem to elevate risk for ADHD-like behaviors, in addition to a host of other (perhaps more legitimately negative?) health outcomes (1, 2, 3).  This is also true for other maternal health issues – like depression or anxiety or even STRESS – not treating them also leads to bad health outcomes for our children.

The only thing that is obvious from these kinds of studies, the only thing that is truly clear: you can hope for a completely uneventful pregnancy, and completely pristine maternal and fetal health throughout, and if you are lucky enough to have that happen? You and your kid (both of whom may or may not have “ideal” health outcomes anyways!) get to be in the reference group! That’s…. it. Hope for that. But don’t count on it.

And if you aren’t that lucky – as nearly all of us are not – please, try not to stress over correlations between health outcomes with low incidences and legitimate medical interventions. Sure, don’t take medicine for no particular reason, of course not. But if you’re asking me if I were pregnant, would I take acetaminophen for a fever, a headache? Absolutely. Without a second thought.

* Amusingly, the authors of the original study state that a prescription for Ritalin “…is a highly specific indicator for an ADHD diagnosis and it has only one additional rare indication  – narcolepsy.” Guess what face I’m making. GUESS.

** I totally made this number up, but it’s close to the real one.

This entry was posted in Grumpy Toxicologist, Science!, soapbox, times when people annoyed me, trawling the interwebs. Bookmark the permalink.

11 Responses to Acetaminophen and ADHD

  1. HereWeGoAJen says:

    This is beautiful. Science! It’s a thing!

    Side note: any idea if there is any major research book on pregnancy like Hale’s book for nursing? Because I would totally buy that one too for the sake of the interwebs.

  2. Arwen says:

    You are brilliant, as usual. Love this.

  3. Paula Reid says:

    Brilliantly done!!!! A sane voice amongst the chaos!

  4. Alexa says:

    I adore you. I have said it many times, but that doesn’t make it any less true.

    The relative/absolute risk issue is maybe the one that most infuriates me in science reporting. My eye starts to twitch when I read “DOUBLES YOUR RISK!!” and then look at the study and see that risk goes from 1% to 2%.

    Also, the “ADHD-like Behavior” makes me raise my eyebrow, because those behavior inventory checklist things have some…flaws.

  5. Aliza says:

    I love your grumpy toxicologist posts. It’s so true that it becomes a “Mom, your duty is to have a child with ABSOLUTELY NO DISEASES OR ANY CONCEIVABLE DEFECT.” Which is impossible. I saw a news story yesterday about increase in certain diseases when Dad is over 45 at the time of conception, but feel like the reporting on that topic doesn’t convey the same “damned if you do, damned if you don’t” that stories about pregnancy and breastfeeding do to moms.

  6. This is wonderful. The absolute risk vs relative risk thing KILLS me.

  7. Sharon says:

    Okay, I usually lurk, but can I give a giant AMEN here!?! I love your posts like this because I know nothing of biology and toxicology etc., so I get to learn that, but I’m a mathematician and science/math reporting is SO. BAD. so much of the time and your posts make me feel like I’m not the only one who cringes at the reporting and its implications.

    Also I am clearly not a writer, so my sentence structure sucks. Sorry ’bout that.

  8. Robin says:

    Statistically speaking, You had me at “The confidence intervals are really wide and overlap a lot with each other, and in many cases, with the non-exposed group.”

    (Especially since there is no mechanism being modelled)

  9. Claire says:

    When I read about this study last week, my first impression was that it was inherently flawed because it did not zero in on amounts and frequencies of Tylenol usage. Thank you for confirming this much more eloquently than I could have.

  10. jen says:

    “I swear I just visualized all of my friends backing out of the room slowly.” This is hilarious. I just stumbled across this post and I love it. It’s so delightfully full of facts and great analysis.

  11. autismepi says:

    This study does have limitations particularly in the exposure assessment, as was stated, but realize just how difficult it is to track usage of an over the counter drug such as acetaminophen. Yes, this study is not perfect but it has some real strengths, it did control for many things including indication for use and maternal psychiatric disorders and it did look at aspirin and ibuprofen and found no effect.

    Also note that this is the second study to find an association between prenatal exposure to acetaminophen and adverse neurodevelopment. The first study utilized the large, prospective Norwegian Birth Cohort and found substantially adverse developmental outcomes in 3 year olds. These included a 70% increased risk of behavioral and motor problems and double the risk of communication problems.

    Additionally, there are numerous studies showing acetaminophen related neurotoxic effects in animals, some with related behavioral abnormalities.

    And these two ecological studies outline temporal and biologic plausibility:

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