Pregnant women’s short-term use of paracetamol may protect the fetus
Paracetamol is the most commonly used medication for pain and fever in both the United States and Europe, and Norway is no exception. The prescription-free sales of paracetamol in Norway correspond to almost two packs per person per year, or an average of 36 tablets in 2016. Pregnant women behave just like the rest: Data from the Norwegian Mother and Child Cohort Study (MoBa) show that approximately 50 percent of them use at least some paracetamol during pregnancy.
While paracetamol is the most commonly used medication, ADHD is the most common mental disorder. Almost 60,000 children are born in Norway every year, and approximately 4 percent of them – nearly 2,400 children – is diagnosed with ADHD before they reach the age of 14. Researchers are now engaged in a massive effort to determine if mother’s use of paracetamol during pregnancy may increase the risk of giving birth to children with a disposition for ADHD.
“When paracetamol is so widely used, and when ADHD is such a common disorder, it is obviously very important to determine if paracetamol can really be the cause of any of these ADHD cases. That's actually what we suspect”, says Eivind Ystrøm. He is an associate professor at the Department of Psychology at the University of Oslo and a researcher at the Norwegian Institute of Public Health.
Researchers found a "smoking gun"
Paracetamol is a widely used active ingredient that is found in drugs like Paracet and Pinex, and it has an analgesic and fever-reducing effect. In 2013, researchers at UiO and the Institute of Public Health found a link between pregnant women's long-term use of paracetamol and an increased incidence of ADHD among their children.
In September 2017, researchers presented a new discovery: They had established an association between mother's long-term use of paracetamol and epigenetic changes in genes that are important for the development of ADHD in children. While the previous studies demonstrated an increased incidence of ADHD in mothers who used paracetamol for more than 28 days during pregnancy, the new studies showed an increased incidence of epigenetic changes in umbilical cord blood in children, when mother had taken paracetamol for more than 20 days.
The problem is that statistical co-variations are not a proof of causality. The researchers are therefore still lacking the final proof in the case against excessive use of paracetamol during pregnancy. Metaphorically, they have found a "smoking gun", but they are not yet 100 percent sure about who is holding the gun.
"We have good reason to suspect that prolonged use of paracetamol during pregnancy leads to an increased risk of ADHD in children. However, our new study shows that short-term use of paracetamol during pregnancy is associated with a reduced incidence of ADHD in children. This is also an important finding”, emphasizes Eivind Ystrøm.
High fever is not good for the fetus
The new study shows that short-term use of paracetamol, for seven days or less during pregnancy, was associated with a 10 per cent reduction in the incidence of ADHD among the children. The new discovery fits well with the results of previous research: If mother suffers from high fever during pregnancy, the fetus may be harmed. The link between mother’s pain and harmful effects on the fetus is harder to explain, but it may be that the prospecting mother’s pain increases the level of stress hormones in her body.
“The results confirm what we have been saying for a lot of years: Pregnant women should use the medicines they need, and it is safe to use paracetamol for short periods during pregnancy. But if you are pregnant and have pain for longer periods of time, you should consult your doctor”, comments Professor Hedvig Nordeng at the UiO’s School of Pharmacy. She is one of the co-authors of the new scientific paper.
A strange link to daddy's use of drugs
In the new study, the researchers found that the incidence of ADHD in children was doubled among women who used paracetamol for more than 29 days during pregnancy. This is consistent with previous findings. But the researchers also found a more unexpected relationship: If the father used a lot of paracetamol in the last three months before mother became pregnant, the incidence of ADHD in the children also doubled.
"We are uncertain about how to interpret this finding. As already mentioned, postdoc Kristina Gervin and researcher Robert Lyle have shown a connection between mother's use of paracetamol and epigenetic changes in the child. If that is the case, it is also possible to imagine that father's use of paracetamol may be associated with epigenetic changes in the sperm he produces”, suggests Ystrøm.
"It may also be that fathers who use a lot of paracetamol in general have a greater genetic risk of ADHD, which they transfer to the child”, he adds.
Paracetamol is the suspect
The researchers examined data from 112 973 children in the Norwegian Mother and Child Cohort Study. A total of 2246 of these children had an ADHD diagnosis, which the researchers found in the database at the Norwegian Patient Registry. A large portion of the mothers – approximately 50 percent –had used paracetamol during pregnancy, most often to reduce fever or moderate pain.
“But the reason for using paracetamol did not matter for the result: Long-term use of paracetamol was nevertheless linked to an increased incidence of ADHD in the children. We also took into account hereditary factors and a number of other risk factors, without finding anything that could impair the relationship between paracetamol and ADHD. All of this reinforces the theory that it may be the long-term drug use that causes the increased incidence of ADHD. We have found nothing to suggest that the increased incidence of ADHD is caused by the disease that was the reason for the use of paracetamol”, says Ystrøm.
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Eivind Ystrøm et al: Prenatal Exposure to Acetaminophen and Risk of ADHD. Pediatrics Volume 140, number 5, November 2017
Kristina Gervin et al.: Long-term prenatal exposure to paracetamol is associated with DNA methylation differences in children diagnosed with ADHD. Clinical Epigenetics, 02 August 2017
Gervin et al. (2016): Cell type specific DNA methylation in cord blood: a 450K-reference data set and cell count-based validation of estimated cell type composition. Epigenetics, 05 Aug 2016.
Vlenterie et al (2016): Neurodevelopmental problems at 18 months among children exposed to paracetamol in utero: a propensity score matched cohort study. International Journal of Epidemiology, August 31, 2016.
Brandlistuen et al (2013): Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. International Journal of Epidemiology, October 24, 2013.
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