Acetaminophen use in pregnancy linked to ADHD in study, but no cause is proven

— -- A new study associates the long-term use of acetaminophen, the active ingredient in over-the-counter pain relievers like Tylenol, during pregnancy with the risk that the children born from those pregnancies could develop attention deficit hyperactivity disorder (ADHD). But many in the medical community say the study, published Monday in the journal Pediatrics, should be taken in stride.

For expecting mothers with pain or fever during pregnancy, acetaminophen has long been the pain reliever of choice. In the U.S., about 65 to 70 percent of pregnant American women say they take acetaminophen-containing products during pregnancy, according to the CDC. Ibuprofen, the other most popular analgesic, isn't recommended in the latter months of pregnancy because of the risk it could harm the fetus.

“Acetaminophen has been used widely in pregnancy,” Dr. Alison Cahill, chief of Maternal-Fetal-Medicine at Washington University in St. Louis, told ABC News. “It’s always important to ask what we know and what we might need to know about the safety of prescription and non-prescription medications in pregnancy.”

Over-the-counter medications containing acetaminophen do not require a prescription, so there’s little control over how much people take at once or how they take it.

And few studies have been done about how drugs taken during pregnancy can affect babies and fetuses; doctors know it is unethical to design a study that hands medications to pregnant women and tells them to take it as part of a trial, particularly if part of what they’re asking is if that the medication could be harmful to the child.

But, research is needed. And because of the large number of women who use acetaminophen during pregnancy, researchers in Norway decided to study the possible risks to the children, looking back at medical records, as well as information from mothers and fathers.

They analyzed a registry of 112,973 children born between 1999 and 2009, including more than 95,000 mothers and 75,000 fathers in Norway. The registry, compiled by the Norwegian Institute of Public Health, used questionnaires given to mothers and fathers during the pregnancy period at multiple time points that asked about their medication use.

The study calculated how many of the children born from those pregnancies were diagnosed with ADHD by searching Norway’s national electronic medical records.

Researchers took risks factors that could also have contributed to ADHD diagnosis into account in the study. They controlled for a number of different possibilities, symptoms of ADHD, depression in the mother, the amount of acetaminophen the mother was using before getting pregnant and the reason she gave for using acetaminophen.

The results of their analysis showed that children of pregnant mothers who used acetaminophen for 29 days total, or more, during the pregnancy were associated with a 220 percent increased risk of ADHD.

Some previous studies have also shown an association between acetaminophen use during pregnancy and ADHD. But the results have not been consistent.

This study, like many others, had a number of issues that limited what researchers and doctors can take away about any connection between ADHD and taking acetaminophen during pregnancy.

“It’s very challenging to do this sort of work,” said Cahill. “It’s unfortunate that this study is not precise enough to draw any conclusions.”

One problem is that how much acetaminophen was used relied on the parents’ self-reporting. The researchers were only able to collect information on the number of days mothers believed they had taken acetaminophen-containing products in their surveys. The study does not account for how many pills, or the total dosage, the mother took in a single day – which is a very important gauge of whether the medicine was used according to directions – and assumed her memory of when and how much she took was accurate.

Since providers can only diagnose ADHD through behavior, since there's no medical test for it, doctors may vary in how -- and if -- they diagnose ADHD. The authors acknowledge that the diagnosis of ADHD was not confirmed in a laboratory, but were simply noted in electronic medical records.

Short-term use of acetaminophen in pregnancy – meaning fewer than 29 total days in this study -- did not show an association with the development of ADHD.

In fact, if the mother used acetaminophen for fewer than eight days, the opposite result appeared to be true: the child had a lower risk of ADHD.

“If the hypothesis is that acetaminophen causes ADHD, but at some level it’s protective, then it really doesn’t make any biological sense,” said Cahill. If the hypothesis were true, investigators would likely have found a dose response.

And another discovery of the study, which cannot yet be explained: the father’s use of acetaminophen in the six months before the pregnancy independently increased the risk of developing ADHD by just over 200 percent.

While it is possible that acetaminophen use alters sperm, such as the authors suggest in their paper, it is also possible that a dad's use might mean that parents have their won higher risk for ADHD, “may be more bothered by pain theoretically...and therefore may take more acetaminophen,” Dr. Mark Wolraich, a pediatrician and chief of the Section of Developmental and Behavioral Pediatrics at Oklahoma University Health Sciences Center, told ABC News.

Many experts caution that it's too early to ask pregnant women to change their behavior based on the findings of this study, including OB/GYN groups.

“This latest study shows no clear evidence that proves a direct relationship between the use of acetaminophen and developmental issues in children,” Dr. Hal Lawrence, executive vice president of the American College of Obstetricians and Gynecologists, told ABC News. “Physicians should not change clinical practice until definitive prospective research is done and, most importantly, patients should not be frightened away from the many benefits of acetaminophen.”

Cahill expresses similar concerns.

“There is an old notion that it is not safe for patients to take the medications that they need during pregnancy,” she said, adding that patients should work with their doctors and specialists to continue treating any medical conditions during pregnancy.

Wolraich suggests similarly that the current findings, “are not strong enough to cause a major warning.”

“This study identifies a possible association. From an association, you can’t necessarily infer a causal relation,” he said. “There may be a third factor that causes the relation to go in either direction."

Therefore, more research is needed before pregnant mothers would be advised to stop or change their usage of acetaminophen products.

“Acetaminophen is generally indicated for pain or temperature,” Wolraich said. “It tends not to be a medication that is essential for taking. To my knowledge, things like low-grade fever are not harmful to the fetus, so if the medication is not essential, one could err on the side of not taking it.”