Acetaminophen should be used sparingly to relieve the aches and pains of pregnancy, according to a review from a group of 91 scientists and medical experts who have called for more research into acetaminophen exposure potentially affecting the development of infants while still in the womb.

Led by University of Massachusetts autism researcher Ann Bauer, the group reviewed 25 years of available data on painkillers in pregnancy, from epidemiological and lab studies, with a goal of increasing awareness among health professionals and pregnant people. 

They say pregnant people should use acetaminophen at "the lowest effective dose for the shortest possible time" and only as recommended, to minimize the possible health risks that have appeared in some studies.

Acetaminophen (also known as paracetamol) is widely considered to be the safest option for relieving mild-to-moderate pain and fever in pregnancy, used by about half of pregnant women worldwide.

Research suggests, however, that most pregnant people use painkillers such as acetaminophen for headaches, muscle pain, back and knee pain when this drug may not actually be that effective in relieving those types of pain.

However, its widespread use is understandable when acetaminophen is one of few medicines available to treat pain and fever, and ibuprofen is not recommended in the later stages of pregnancy.

Concerns about using acetaminophen in pregnancy have arisen against a backdrop of rising rates of developmental disorders in children (although this might actually be a reflection of greater recognition and awareness of conditions such as autism that exist on a spectrum).

Acetaminophen is classed as an endocrine disruptor, capable of interfering with hormones needed for healthy development. But whether or not acetaminophen exposure in the womb actually leads to behavioral or developmental disorders remains unclear when a host of genetic and environmental factors are also in play.

Until the risks are fully known and explored, "we should reduce our use of acetaminophen when possible throughout the entire pregnancy," Bauer told STAT News.

In their review of evidence published to date, Bauer and colleagues synthesized data from epidemiology studies on acetaminophen use in pregnancy, as well as animal research and lab-grown cell experiments published over 25 years, from 1995 to 2020.

The group cautions using painkillers in pregnancy, saying doctors should counsel people early in their pregnancy about how to limit acetaminophen use. But caution is also needed in interpreting the results of this review.

Focusing on the research involving people, some 26 of 29 observational studies – which included over 220,000 mother-child pairs – found evidence to suggest exposure to acetaminophen in utero may be connected with neurodevelopmental outcomes in kids, such as attention deficit hyperactivity disorder (ADHD), hyperactivity, and behavioral difficulties.

Fewer studies looked at patterns of acetaminophen use and dosages, but did suggest a greater risk of developmental disorders with repeated use of painkillers in pregnancy.

A handful of observational studies also suggested a link may exist between acetaminophen use in pregnancy and urogenital and reproductive tract abnormalities in boys.

"Based on this research, we believe we know enough to be concerned about the potential developmental risks associated with prenatal [acetaminophen] exposure .. and therefore call for precautionary action," Bauer and colleagues write in their statement.

But Sarah Stock, a specialist in maternal and fetal medicine at the University of Edinburgh, says much of the evidence reviewed is "not robust enough to draw any conclusions that acetaminophen use in pregnancy, especially occasional use, causes developmental problems in humans."

While some of the cited studies used data from medical records, most relied on parents reporting their child's developmental outcomes, and on pregnant people reporting how often they take pain relief medications.

It is also "impossible", Stock says, "to disentangle whether it is conditions that cause people to take acetaminophen at high doses for long periods of time, or acetaminophen itself, that might have a link to developmental problems".

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) stated, in 2015 and 2019, respectively, that studies investigating a possible connection between acetaminophen use in pregnancy and disorders in kids were "inconclusive".

But the group who authored the statement is calling on medical authorities to review the most recent research and reconsider their recommendations to doctors.

That might be reasonable, says Stephen Evans, a pharmacoepidemiologist at London School of Hygiene & Tropical Medicine, but "it is not a message for current or prospective pregnant mothers" and "raising anxiety should also be discouraged."

Other medical scientists agree with Evans that the epidemiological studies cited in the review are, on the whole, inconsistent.

"The evidence that paracetamol is harmful is not strong but observations in humans regarding possible developmental issues are supported by animal studies," says obstetrician Andrew Shennan of King's College London, who was also not involved in the review.  

"Prudent surveillance and more research should continue but paracetamol can be used to treat pain and fevers in pregnancy."

It's also important to note that while the research reviewed by Bauer and colleagues is substantial, it did not include data on pregnancy in transgender men, non-binary people or intersex people – diversity which should be recognized in future research studies.

Nonetheless, the message for mothers and people considering pregnancy hasn't changed: consult your doctor before taking any medication in pregnancy, and use only as needed.

"Pregnant or not, no-one should take a medication unnecessarily, for longer than necessary or at a higher dose than needed," Stock says.

The statement was published in Nature Reviews Endocrinology along with an editorial from the journal.