Should You Avoid Acetaminophen During Pregnancy
With the big push in recent years to reduce prescription opioid use by patients, nonsteroidal anti-inflammatories and acetaminophen (Tylenol) have been the mainstay for pain relief for many patients. Although in general, we recommend that pregnant women avoid all medications that are not required for a specific medical reason, the American College of OB/GYN and most obstetricians across the United States have told patients that Tylenol is a safe pain reliever to use during pregnancy.
However, there have been multiple studies suggesting that there may be an increased risk of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) in the infants of women who used acetaminophen during pregnancy.
Most consumers believe that over-the-counter medications are both helpful and safe even during pregnancy. As our familiarity with an over-the-counter medication increases, so does our impression of the safety and efficacy of those products.
Yet, another study published in January 2024 found an increased risk of attention deficit hyperactivity disorder (ADHD) in children when mothers used acetaminophen, particularly during the second trimester.
According to the Centers for Disease Control and Prevention, roughly 6 million children aged 3 to 17 years were diagnosed with ADHD. This is 9.8% of the children in that age range. Even more concerning is that the that number rose dramatically between 2003 and 2011, from 4.4% to 6.4% of the general population.
ADHD is a neurodevelopmental disorder that affects an individual's ability to manage their attention, stay organized, and control their behavior. Data also show that 64% of those with ADHD also have at least one other mental, emotional, or behavioral disorder.
History of Acetaminophen
Acetaminophen was discovered in 1878 and in the early 1950s researchers demonstrated that it worked as well as aspirin with fewer side effects for pain relief and fever reduction. It was brought into the market in 1955 as the over-the-counter medication Tylenol, and by the early 1980s, Tylenol was the top selling pain reliever in the United States. Acetaminophen is now used in more than 600 over-the-counter and prescription medications including combination products for sleep, coughs, colds and allergies. When acetaminophen was approved in the 1950s, preclinical testing for reproductive safety was not required by the FDA.
The gold standard for understanding the effect of the medication is to randomly assign one group to take the drug and another to get a placebo with neither the researchers nor the participants knowing who got what until the end of the study. This is called a randomized double-blind placebo-controlled study. This has never been done with Tylenol and I can assure you it will never be done. Therefore, all data on the potential effects of acetaminophen has come from observational studies and laboratory animal experiments.
One of the more common uses of acetaminophen is to relieve fever. There is strong evidence from both lab animal studies and human studies that have associated a high fever during early pregnancy with an increased risk of birth defects and miscarriages.
Some common over-the-counter drugs used to treat both fever and pain are aspirin, ibuprofen and naproxen, but the FDA has warned against using any of these after 20 weeks of pregnancy because of an increased risk of damage to the baby's kidneys. The chronic use of opioids for pain relief during pregnancy is associated with poor fetal growth, preterm delivery and neonatal opioid withdrawal syndrome.
Medicinal cannabis is increasingly being used by women during pregnancy who think of it as a natural and therefore safe alternative for pain management and control of nausea and vomiting of pregnancy. Unfortunately, there is little data on the safety of cannabis products and recent studies suggest that infants born from women with chronic use during pregnancy have neurological developmental problems. We strongly recommend against the use of cannabis products during pregnancy.
Because of the issues with the above alternative options, acetaminophen has become a commonly used medication during pregnancy. However, there have been multiple observational studies that have questioned the safety of acetaminophen during pregnancy. I will review some of those in this report.
Studies Linking Acetaminophen to Neurodevelopmental Disorders
A 2019 study was compiled by analyzing data from the Boston Birth Cohort, a long-term study of factors influencing pregnancy and child development. They collected umbilical cord blood from nearly 1000 births and measured the amount of acetaminophen in the samples. By the time the children were an average of 8.9 years old, 25.8% had been diagnosed with ADHD alone, 6.6% with ASD alone and 4.2% with both ADHD and ASD. When they looked at the amount of acetaminophen from lowest to highest, the middle third of exposure was associated with 2.26 times the risk for ADHD and the highest third of exposure was associated with 2.86 times the risk. Similarly, ASD risk was higher for those in the middle third (2.14 times) and highest third (3.62 times). It is not clear in the study whether these mothers took Tylenol throughout pregnancy or only at the end of pregnancy. More importantly, looking at the cord blood acetaminophen level would have only been looking at infants who were exposed to in utero acetaminophen shortly before delivery as acetaminophen lingers in the blood for only a few hours.
It is important to realize that this is not a study that confirms acetaminophens causation of ADHD and ASD. It is only a study that shows a correlation between prenatal exposure and these developmental neurologic conditions. Measurement of acetaminophen in the cord blood would imply that a single dose right before birth could have a dramatic effect on brain development which is highly implausible.
Other observational studies also showed a correlation between prenatal exposure and ADHD and ASD.
In a 2020 study, epidemiologists explored whether confounding factors such as hereditary and maternal illness could bias acetaminophen research. Their data initially found a 35% increased likelihood of ADHD in children exposed to prenatal acetaminophen. But when they stringently adjusted for parental ADHD, migraines and depression in the mother, the ADHD risk disappeared.
Nevertheless, in 2021, an international group of 91 scientists and clinicians declared that the current research, limited as it was, warranted stronger warnings about the use of acetaminophen during pregnancy. In a consensus statement published in Nature Reviews Endocrinology, they called for increased awareness of the drug’s potential risks and additional focused research studies to clarify those risks. It is also important to note that there were numerous professional groups including American College of Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine who felt that the consensus opinion was based on flawed data that exaggerated the potential harms of acetaminophen.
A more recent paper published in January 2024 to support data that acetaminophen during pregnancy could affect neurological development in children was part of the Illinois Kids Development Study that involved tracking prenatal chemical exposure. The data showed that in women who had higher acetaminophen usage during the second trimester, had children with an increase in ADHD-type behavior.
The researchers used the Child Behavior Checklist (CBCL) to identify behaviors associated with attention deficit and found increased scores at ages 2, 3 and 4 years. The association appeared to be dose-related, as women with higher exposure during the second trimester had children with higher CBCL scores for ADHD. This study included 300 children.
One difference between this study about exposure to acetaminophen during pregnancy and past studies was that researchers in this study asked pregnant women about acetaminophen use six times during their pregnancy while in other studies they were asked at most once per trimester or only retrospectively after delivery.
Some of the unanswered questions are whether acetaminophen during early pregnancy and more importantly only rare use of acetaminophen are also risk factors for ADHD and ASD.
Resolution of this debate is of great significance since acetaminophen is one of the most commonly used drugs in the world and in the United States up to 65% of all pregnant women have used it during their pregnancies.
April 9, 2024 Study on Acetaminophen Use during Pregnancy
The most recent study to be published regarding acetaminophen use during pregnancy and children's risk of autism, ADHD and intellectual disability was published in JAMA (Journal of the American Medical Association). This was a nationwide study with sibling control analysis sampling 2,480,797 children born in 19 95-2019 in Sweden with a more than 2-year follow-up.
The data was collected prospectively which is important because that avoids recall bias objection to retrospective studies. Women who have a child with an abnormality are perhaps more likely to recall any medication they might have taken during pregnancy hoping to have an explanation for their child's problems.
They found that 185,909 children (7.49%) were exposed to acetaminophen during pregnancy. The crude risk for those not exposed versus those exposed to acetaminophen were 1.33% versus 1.53% for autism, 2.46% versus 2.87% for ADHD and 0.70% versus 0.82% for intellectual disability.
Therefore, in the crude evaluation, acetaminophen use during pregnancy was associated with an increased risk of these neurodevelopmental disorders.
To address confounding, matched sibling pairs were also analyzed. Sibling control analyses found no evidence of acetaminophen use during pregnancy been associated with autism, ADHD or intellectual disabilities. Similarly, there was no evidence of a dose response pattern. For example, for autism, compared with no use of acetaminophen, persons with low (<20 5th percentile), medium (25th-75th percentile) and high (>70 5th percentile close (mean daily acetaminophen use had risk values of 0.85, 0.96 and 0.88 respectively.
The strengths of this study include: firstly, a very large number of children, secondly, prospective determination of acetaminophen exposure, and thirdly, the use of sibling control. Their conclusions are that acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD or intellectual disability. The authors suggest that the associations observed in prior studies may have been attributable to familial confounding. That is to say because of their genetics, some families may be more prone to neurodevelopmental disorders.
I am sure that this study will not be the end of this debate; however, it does provide a large measure of reassurance that the risks of acetaminophen may be minimal at best.
CONCLUSION
So, what are we left with? The best opinion is that for pregnant women experiencing fever or pain, acetaminophen is still the best option. However, it should be used only when indicated and in the lowestdose for the shortest duration.
