An international group of 13 scientists has released a statement calling for the health care community to carefully consider the use of acetaminophen (APAP) during pregnancy until the painkiller is thoroughly investigated for any potential impact on fetal development in the womb. Outside the United States, acetaminophen is known as paracetamol.
According to the statement published Thursday in the journal Nature Reviews Endocrinology, a growing body of research shows that “prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders.”
The statement is not health guidance, but urges health care providers and regulators to take action.
“The authors are not recommending anything counter to what is already done by obstetrician-gynecologists when prescribing acetaminophen for a given clinical condition,” said Dr. Christopher Zahn, vice president of practice activities for the American College of Obstetricians and Gynecologists, who was not involved in the statement.
“However, as always, any medication taken during pregnancy should be used only as needed, in moderation, and after the pregnant patient has consulted with their doctor,” he added.
‘Medically indicated’
Signed by 91 scientists from Australia, Brazil, Canada, Europe, Israel, Scotland, the UK and US, the consensus statement calls for pregnant women to be cautioned to “forgo use” of acetaminophen during pregnancy “unless its use is medically indicated.”
Even after getting approval from a physician, the statement said, women should “minimize exposure by using the lowest effective dose for the shortest possible time.”
“There are good medical reasons for pregnant women to use APAP, after consulting physicians or pharmacists, and that is for fever and severe pain,” said David Kristensen, an associate professor of cell biology and physiology at the University of Copenhagen and one of the 13 co-authors of the statement.
High fever is a known risk for multiple fetal disorders, “including neural tube defects and later life cardiovascular disorders,” the statement noted.
However, studies show only a third of pregnant women use acetaminophen to treat fever, the statement added. Instead, “headache, muscle pain, back pain and infection” were the most common reasons for use.
“Data suggests more than 50% of women worldwide are using APAP during their pregnancies,” Kristensen said. “Many of these women do not consider APAP as a true medication that can have potential side effects.
“It is those women who do not consider it as a true medication that we are trying to reach and want them to reflect a moment on their use,” he added.
Limited options
Acetaminophen has been the only pain reliever generally considered safe for use throughout pregnancy, which leaves mothers-to-be with few medical options if it is shown to be harmful to a fetus.
“Ibuprofen has already been linked with birth defects and damage to the baby’s heart and blood vessels,” while high doses of aspirin have been linked to “bleeding in the brain and congenital defects,” said pediatrician Dr. Leonardo Trasande, director of environmental pediatrics at NYU Langone Health, who was not involved with the creation of the statement.
“Research on acetaminophen shows this is an emerging field of concern,” Trasande said. “I’m always going to say that further research is needed to understand the mechanisms and to control for other exposures. But the fact is there is substantial evidence to suggest that at the very least, this is a hazard for the fetus.”
Melissa Muñoz, the media relations director for Johnson & Johnson, told CNN in an email that “the label on our adult TYLENOL® products, in which acetaminophen is the active ingredient, states, “If pregnant or breast-feeding, ask a health professional before use.
“The current evidence does not support a causal link between acetaminophen use during pregnancy and the risk of adverse neurological, urogenital and reproductive outcomes. Consumers who have medical concerns or questions about acetaminophen should contact their health care professional.”
In their analysis of existing research on acetaminophen, the authors of the statement found that short term use – two weeks or less – carried the least risk.
“It is among the women reporting use for a longer duration – about two weeks or over two weeks during pregnancy – that’s where the strongest associations are,” Kristensen said.
Those results suggest that “short-term use may be less of a risk, which gives healthcare providers and pregnant women some reassuring leeway for the occasional use of APAP,” said Jane Houlihan, research director for Healthy Babies Bright Futures, an alliance of non-profit organizations which tracks babies’ exposures to toxic chemicals that harm brain development.
Reproductive and neurological impact
Scientists have been studying the potential impact of acetaminophen on the developing fetus for some time. One reason is a similarity between APAP and a group of synthetic chemicals called phthalates, which are found in hundreds of auto, home, food and personal care items.
“Acetaminophen’s chemical structure and the way it breaks down seems to have a similar backbone to phthalates,” said NYU’s Trasande, who researches the impact of chemicals on babies. In their analysis of the studies.
Lab studies, animal research and 29 studies of acetaminophen use in 220,000 mother and child pairs have been done, the statement said, including two studies that found acetaminophen in cord blood and meconium, the baby’s first stool.
“There is now a significant body of evidence that suggests that APAP disrupts the reproductive development of animals and humans,” said co-author Shanna Swan, a professor of environmental medicine and public health at the Icahn School of Medicine at Mount Sinai in New York.
“There’s enough evidence to find increased risk of undescended testicles and a shortening of the ano-genital distance, which is a predictive of later decreased sperm count and decreased fertility,” Swan said. “We also see impaired ovarian function which has consequences for later fertility, although females have been less studied.”
Twenty-six of the mother and child studies found a link between acetaminophen exposure during pregnancy and neurodevelopmental outcomes, the statement noted.
“The identified disorders were primarily attention deficit hyperactivity disorder, or ADHD, and related ADHD behavior abnormalities that also include autism spectrum disorder, language delays, decreased IQ and conduct disorders,” said co-author Ann Bauer, a postdoctoral fellow and researcher at the Center for Autism Research & Education at UMass Lowell.
Research needed
ACOG’s Zahn disagreed with the statement’s conclusions.
“This consensus statement, and studies that have been conducted in the past, show no clear evidence that proves a direct relationship between the prudent use of acetaminophen during any trimester and fetal developmental issues,” ACOG’s Zahn said.
“Neurodevelopmental disorders, in particular, are multifactorial and very difficult to associate with a singular cause,” Zahn continued. “The brain does not stop developing until at least 15 months of age, which leaves room for children to be exposed to a number of factors that could potentially lead to these issues.”
There are many areas that need further study, according to the statement, which is why the group is calling for a massive research effort – while at the same time cautioning pregnant women against using acetaminophen without medical supervision.
“The ideal human study has not been done,” Swan said, adding that more objective measures of when during pregnancy and how long a baby was exposed are needed.
“And then we have to follow these children, and look not only at their general development at birth and 1 year of age, but also how was their neurodevelopment over time. Then I think we’d clear up a lot of these uncertainties.”
