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Acetaminophen, sold as Tylenol and many generic formulations, is widely considered safe to take during pregnancy. But a new study reports that children of women who do so have a higher risk of behavioral problems when they’re about 7 than do children whose pregnant mothers never took the pain drug.
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This is a pretty straightforward observational study, published Monday in JAMA Pediatrics. Researchers mined data collected by the long-running ALSPAC study in England, which in 1991 began recruiting pregnant women and has gathered years of data (via clinic visits and questionnaires) on their children’s health. There were 7,796 mother-child pairs in this study.
Among the information collected: Did the women take acetaminophen while pregnant? By their fourth month, 53 percent reported doing so at any point in the previous three months; by their seventh month, 42 percent did. When the children were 7, their mothers answered a questionnaire about their children’s behavior, including conduct problems, peer relationships, emotional difficulties, and hyperactivity.
Children whose mothers took acetaminophen by the 18th week of pregnancy were 16 percent more likely to have behavioral difficulties at age 7, epidemiologist Evie Stergiakouli of England’s University of Bristol and her colleagues reported. Children whose mothers took acetaminophen by their 32nd week were 46 percent more likely to have such difficulties.
It’s always important to know the absolute risk, since something like “a 46 percent greater risk of behavioral difficulties” sounds alarming. In this case, those numbers are more modest. Among 7-year-olds whose mothers took acetaminophen during their second or third trimester, 6.3 percent had overall behavioral difficulties, while 4.3 percent of those whose mothers did not take the drug had such problems. Some of the components of those difficulties: 12.3 percent vs. 8.8 percent for conduct problems, and 7.1 percent vs. 6.5 percent for problems with peer relationships.
The size of the study and the care the researchers took to control for things such as maternal smoking and drinking — and even genetic factors — is impressive, said Dr. Yona Amitai of Israel’s Bar-Ilan University, an expert in pediatrics and toxicology who was not involved in the study, calling it “well conducted.” And the calculations seem solid.
But the study matters only if the association between mom’s taking acetaminophen during pregnancy and her child’s behavioral problems is causal and not a coincidence — which is always a possibility in observational studies.
There are reasons to doubt that children’s behavioral problems were caused by exposure to acetaminophen before birth. For one thing, for 6 of the 12 behavioral measurements (conduct problems, hyperactivity, and the like), statistical analysis showed it was quite possible the risk went the other way: that is, that mom’s acetaminophen use decreased the chances of the child’s having these problems.
Of greater concern is what are called confounding factors, said Amitai. That means that although the researchers measured an association between kids’ behavioral problems and moms’ acetaminophen use, something else might also have been in play. The study did control for mothers’ smoking, drinking, age, self-reported psychiatric illnesses, ADHD genes, pain or fever (reasons for taking acetaminophen), and socioeconomic status. But “women who took acetaminophen during pregnancy might also be different from those who did not,” Amitai said.
The study did not control for some of the most significant influences on prenatal brain development and childhood behavior: mothers’ fish consumption during pregnancy (which ALSPAC and other studies have shown reduces the risk of hyperactivity and other behavioral problems, while promoting brain development) and their IQ and education. It’s therefore possible that the actual cause of the ALSPAC children’s behavioral problems was, for instance, their mothers’ low fish consumption or low education levels.
As always with a study that asks people to remember what they did in the past (did you take acetaminophen?), fallible memories can also produce misleading results. And there were no data on how much acetaminophen mothers-to-be took, or how often, and therefore no way to check whether more was associated with worse problems for their kids — which, if true, adds to an association’s credibility.
Stergiakouli told STAT that she and her colleagues dealt with potential confounding factors by measuring acetaminophen use by women after they gave birth. Their study “is robust to these confounding factors,” she said, and was conducted by top-notch epidemiologists who “specialize in examining if observational associations are causal.”
Experts at the American College of Obstetricians and Gynecologists said the study fell short of showing a convincing association between acetaminophen and behavioral problems in children. ACOG has “always identified acetaminophen as one of the only safe pain relievers for women during pregnancy,” said CEO Dr. Hal Lawrence. The new study presents “no clear evidence [of] a direct relationship between the prudent use of acetaminophen during any trimester and developmental issues in children.”
Stergiakouli agreed. “Pregnant women should still use acetaminophen as required because there is a risk of not treating fever or pain during pregnancy,” she said.
The new study falls far short of showing that taking acetaminophen during pregnancy increases children’s risk of behavioral problems.