Acetaminophen during pregnancy is associated with ADHD

A large study recently published in the journal Pediatrics finds further evidence of a link between prenatal acetaminophen usage and attention deficit hyperactivity disorder.

According to some studies, attention deficit hyperactivity disorder (ADHD) is becoming increasingly common. Why this is the case is not known; the causes and risk factors beneath ADHD are only slowly being unraveled.

Some of the increase is due to improvements in diagnosis and changes in how the condition is assessed, but it seems that these factors alone cannot explain the size of the growth.

Recently, some scientists have focused on acetaminophen use during pregnancy as a potential factor. This over-the-counter medication is deemed relatively safe to use during pregnancy and is recommended to ease fever and pain.

Acetaminophen is used by up to 70 percent of women during pregnancy in the United States, and between 50 and 60 percent of pregnant women across Western and Northern Europe. Potential links between this common OTC drug and ADHD have faced increasing scrutiny in recent years.

Acetaminophen and ADHD research
A Norwegian study published in 2013 found that babies whose mothers had taken acetaminophen for 28 days or more during pregnancy had motor and cognitive deficits at 3 years old.

Similarly, in 2014, a Danish study found links between prenatal acetaminophen use and both a clinical ADHD diagnosis and ADHD symptoms in offspring at the age of 7.

These studies fueled further research, and a number of papers on the matter were published. One of these demonstrated a relationship between the use of acetaminophen during pregnancy and "ADHD-like behavior" in the offspring at the ages of 7 and 11.

Although evidence is mounting, many of the earlier studies had flaws. For instance, acetaminophen is recommended for pregnant women who have existing health issues, such as inflammatory and autoimmune diseases. These condition types themselves are linked with neurodevelopmental disorders in offspring. So it may be the underlying illness to blame, and not acetaminophen.

Another issue is that acetaminophen use in pregnancy has been linked to maternal impulsivity. This means that there could be genes at work that cause impulsive behavior in the mother and potentially influence the development of ADHD in the offspring.

In the most recent study, the researchers looked to iron out some of these potentially confounding variables. For instance, they controlled for ADHD-like symptoms in the parents as well as maternal depression, which has been considered a potential risk factor for ADHD.

They also looked at the role of male acetaminophen usage. In earlier studies, it was suggested that acetaminophen can interrupt endocrine processes in the testis, potentially influencing the brain development of their future children.

Data were taken from the Norwegian Mother and Child Cohort Study, including 114,744 children who were born between 1999 and 2009, as well as 95,242 mothers and 75,217 fathers. Of the mothers, almost half (52,707) used acetaminophen during pregnancy.

The research team discovered that acetaminophen use for 7 days or fewer during pregnancy was negatively associated with ADHD. However, for longer than 7 days, the risk of ADHD increased with longer periods of use.

The children of mothers who had used acetaminophen for 29 days had more than double the risk of developing ADHD. Also, children of mothers who took acetaminophen for fevers and infections for 22–28 days were more than six times more likely to have an ADHD diagnosis.

Even after adjusting for multiple factors — including ADHD symptoms in the parents — the raised ADHD risk was still significant.

When looking at the data from the fathers, they found that those who had taken acetaminophen for 29 or more days before conception fathered twice as many children with ADHD. The authors write:

"The association between paternal pre-conceptional acetaminophen use and ADHD was similar to the association between maternal use of acetaminophen during pregnancy and ADHD."
 
Because the study is observational, it is not possible to prove cause and effect. However, the study was careful to eliminate as many confounding variables as possible, and its findings are in line with previous work.

There are a number of theories as to how acetaminophen might influence ADHD outcomes in the unborn child. The authors mention three potential pathways.

In a mouse model, maternal acetaminophen exposure increased levels of brain-derived neurotrophic factor, resulting in altered behavior.

Acetaminophen could potentially interrupt brain development through oxidative stress, which leads to the death of neurons.

But for now, it is unclear whether some, all, or none of these mechanisms are important. Much more study will be needed. However, because acetaminophen is so widely used, and because ADHD is currently in the spotlight, answers are sure to follow.

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