Pharmacists are among the most accessible of health professionals, and so we receive a lot of questions from the public. No appointment required, and the advice is free. Among the most frequent sources of questions are women seeking advice on drug use in pregnancy. This is an area where some health professionals are reluctant to tread. Some prefer to redirect all of these questions to physicians. But physicians are not always easily accessible, and few want to make an appointment just to ask what appears to be a simple question: Is it safe, or not? Admittedly, addressing questions about drug use in pregnancy can be challenging. There are no randomized controlled trials we can look to — there’s only messier, less definitive data. Our responses are filled with cautious hedging about risk and benefit, describing what we know (and don’t know) about fetal effects. In the pharmacy, one of the most common questions from pregnant women is about the use of acetaminophen (aka paracetamol aka APAP), more commonly known by the brand name Tylenol. Google “Tylenol and pregnancy” and you get 4.8 million results. Which source should you trust?
It should come as no surprise that acetaminophen has been the topic of several past posts. It’s one of the most commonly-used medicines worldwide, starting in infancy for fever, right through towards end-of-life pain control in the elderly. As an ingredient, acetaminophen is packaged into hundreds of prescription and non-prescription drugs. Acetaminophen has a good safety profile when used appropriately. However it is among the most harmful of drugs in overdose, and the ease at which overdose can occur makes acetaminophen the cause of hundreds of cases of liver failure per year. Given this frequency of use, and a unique risk profile, there are continued questions about its safety and efficacy. Regulators (and manufacturers) continue to experiment with ways to make the drug available, while minimizing the risk of unintentional harm.
Pain in pregnancy, and the desire to treat it, is common. Beyond the non-pregnancy causes everyone can experience, like headaches and colds, the pregnant body is undergoing a rapid transformation that may not be painless. Weight gain of 25 or more pounds leads to posture changes and painful joints from head to toe. Low back pain is common, and it can be worse at night, leading to insomnia. Pelvis pain, knee pain, and hip pain are also common, and can be quite debilitating. While non-drug measures should always be attempted before considering drug treatment, severe or prolonged pregnancy pain may require the consideration of drug treatment.
Acetaminophen is the current go-to drug for pain control in pregnancy. There is good evidence to show that it does not increase the risk of major birth defects above the baseline risk (2-3%) that is inherent to any pregnancy. Acetaminophen can be used throughout pregnancy, and as long as the dosing is appropriate, side effects are remarkably rare. With a safe history of use and a low risk of side effects, acetaminophen is widely used when pain control with drugs is required.
The risks and benefits of drug use in pregnancy can’t be looked at in isolation. There is always an alternative, and the relative risks and benefits must be weighed. Doing nothing is always an alternative for pain, so the consequences of untreated pain need to be considered. But when pain is severe, other drugs might be considered. Stacked up against the alternatives, acetaminophen looks pretty good. Anti-inflammatory drugs like ibuprofen must be avoided in the later stages of pregnancy, due to the concerns about cardiovascular toxicity. Compared to the anti-inflammatory drugs, acetaminophen is unlikely to cause gastrointestinal ulcers, blood disorders, or kidney problems. Nor does acetaminophen appear to increase the risk of cardiovascular events such as heart attacks and strokes. Compared to the anti-inflammatory drugs, acetaminophen also has few interactions with other drugs, so it can safely be used for pain relief in pregnant women on other medications, or with other medical conditions where other pain relievers might have unwanted effects.
Beyond acetaminophen and the anti-inflammatories are the narcotics. The addictive properties of narcotics are well known, and they affect the fetus, too. Compared to a drug like codeine or morphine, acetaminophen provides a non-addictive alternative that may be more appropriate for short-term or long-term pain issues when drug treatment is being considered.
Now there’s a new study suggesting that the risk and benefit of acetaminophen in pregnancy may not be so clear. The paper is from JAMA Pediatrics, and it’s entitled “Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders”. Zeyan Liew and colleagues conducted a study of over 64,000 children and mothers who were enrolled in the Danish National Birth Cohort between 1996 and 2002. The Cohort was established to ask (and answer) questions about pregnancy and early childhood and the relationship to diseases that emerge later in life. Pregnant women were recruited with the intention to conduct long-term studies as these women (and their children) age.
The design of the study was straightforward. Acetaminophen use was assessed through telephone interviews before and after birth. Measurements of ADHD and hyperkinetic disorders after birth were measured by:
- using a standardized questionnaire in parents once children reached age 7
- looked for hyperkinetic disorder diagnoses in hospital and psychiatric registries
- looked for prescriptions for ADHD medications through a national registry
Not surprisingly for a drug that is recommended for use in pregnancy, more than half of all of the study’s participants used acetaminophen at some point during pregnancy. There was a relationship found: Children whose mother used acetaminophen during pregnancy had a higher risk of a hospital diagnosis of HKD (hazard ratio 1.37, confidence intervals 1.19-1.59), receipt of ADHD medication (hazard ratio 1.29, confidence intervals 1.15-1.44) or having ADHD-like behaviors as defined by the standardized questionnaire (hazard ratio 1.01-1.27). There was also a positive relationship with the number of trimesters of use. Numerous confounders were studied and there was no relationship found.
There are a lot of strengths to this study that merit a close consideration of the findings. It’s a big data set that was powerful enough to detect a very subtle difference. The analysis was generally very well done. It was prospective, so the risk of bias due to time and memory (“recall bias”) was minimal. There were three independent data points collected, and two (hospital diagnoses and prescriptions) were objective measurements. There was a consistent trend observed: The risks appeared higher with use in more than one trimester, and when the duration of use (in weeks) increased. This was observed across the different endpoints. We can never say correlation equals causation with a non-randomized study, but does this study suggest it’s time to change the guidance on acetaminophen?
There were a few important limitations. Investigators failed to fully evaluate the family history of behavior disorders in parents. In diseases where there is good evidence for genetics having a substantial role, this is a significant limitation. The use of ADHD-prescriptions may not be a great measure either, given the lack of certainty about the diagnosis of ADHD (although this should have affected both groups equally). It could also be that acetaminophen use is just a signal or proxy for something else — and the acetaminophen is just what we’re noticing, and not the actual cause. It could be another condition or cause that the pregnant women are taking acetaminophen for. Finally there’s considerable uncertainty about the dosing and timing. The measurements of exposure was not ideal — in some cases it had to be estimated for women who could not recall when they took the drug. In addition, the overall dosing (e.g., average number of tablets) wasn’t available).
Probably the biggest fault to the study isn’t actually a flaw — it’s one of how meaningful these results really are. The absolute risks of ADHD remain tiny. Most of the headlines mention the relative risk: (“30% MORE LIKELY TO EXHIBIT ADHD”) when it’s the absolute risk that needs to be considered. The biggest difference as measured at age seven was the variation in the standardized questionnaire: 34 per 1 000 in the group “ever took acetaminophen”, versus 25 per 1 000 in the “never took acetaminophen” group. Recall, that’s a survey result — not a diagnosis. On balance, if the effect is real, it very minor, and the vast majority of the cases of ADHD are being detected in women who took no acetaminophen at all.
I have mixed feelings about these studies. On one hand, these databases give us the ability to evaluate very subtle effects that we could never otherwise identify. They also allow us to make inferences about relationships when randomization isn’t feasible or even ethically possible. And they may lead to further studies to help us better understand risk and benefit. When it comes to acetaminophen and ADHD, we can be reassured that if there is any causal effect from acetaminophen, then the effect is very slight. There’s no evidence to suggest that acetaminophen is driving the perception of growing incidence of ADHD. And studies like these are also a reminder to health professionals that we cannot take anything for granted — we need to look carefully yet critically at any new evidence. But there’s a downside to studies like these. Unwarranted panic is one, often driven by reporting that hypes the “statistically significant” without providing insight and context. Pushing women towards other, less safe alternatives could cause more harm.
Does the study change how we manage pain in pregnancy? It shouldn’t. No drug should be taken in pregnancy unless it’s necessary — acetaminophen is no exception. But there’s no reason for pregnant women to suffer from pain unnecessarily. Acetaminophen remains the drug of choice when pain control is necessary in pregnancy.
Liew Z., Ritz B., Rebordosa C., Lee P.C. & Olsen J. Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders, JAMA Pediatrics, DOI: 10.1001/jamapediatrics.2013.4914