A study links prenatal acetaminophen with reproductive changes in girls. Doctors say it remains safe to use when needed

A new study found that some girls born to mothers who took acetaminophen during pregnancy developed reproductive organ changes that could affect fertility later in life. It’s a finding the study authors say should drive future research but shouldn’t yet change how certain symptoms are treated during pregnancy. (Credit: teerawut111/iStockphoto/Getty Images via CNN Newsource)

A new study found that some girls born to mothers who took acetaminophen during pregnancy developed reproductive organ changes that could affect fertility later in life. It’s a finding the study authors say should drive future research but shouldn’t yet change how certain symptoms are treated during pregnancy.

The new research doesn’t show that acetaminophen, also known as paracetamol or Tylenol, caused the reproductive changes. Women shouldn’t be “alarmed” by the findings because the research does not establish cause and effect, study co-author Dr. Margit Bistrup Fischer said.

It also does not mean pregnant women should stop taking acetaminophen if they need it, she noted, but “it’s definitely something we need as a society to talk about and inform pregnant women more about, so they can make an informed decision.”

Acetaminophen has long been known as the safest over-the-counter option to treat fever or pain during pregnancy, although doctors advise using it in moderation and only when necessary. An untreated fever can endanger both mother and fetus, possibly leading to birth defects or miscarriage.

Much more research is needed to determine whether it’s the over-the-counter medicine itself causing the changes or something else, said Fischer, a postdoctoral researcher in the Department of Growth and Reproduction at the Rigshospitalet in Copenhagen, Denmark.

The American College of Obstetricians and Gynecologists agreed that more study is needed, saying in a statement that the findings “do not indicate that current clinical recommendations should change. Consistent with ACOG’s existing guidance, acetaminophen remains one of the only safe medications that can be used during pregnancy when indicated, and patients should consult their obstetric care professional before making any changes to medication use.”

Acetaminophen use during pregnancy became a hot-button issue last year when U.S. President Donald Trump told pregnant women with pain or fever to “tough it out” and avoid acetaminophen if possible, blaming, without evidence, the medicine and certain vaccines for autism.

Last year, the U.S. Food and Drug Administration initiated a label change suggesting that acetaminophen use during pregnancy could put the fetus at risk of neurological conditions and alerted doctors that acetaminophen use during pregnancy can be associated with a “very increased risk of autism,” despite decades of evidence that it does not cause neurological problems and unsettled science on the connection between the medicine and autism.

Acetaminophen is the only over-the-counter drug that doctors and medical societies recommend pregnant people take for pain or fever, but organizations such as the American College of Obstetricians and Gynecologists advise using it only as needed, in moderation and after patients talk to their doctors. Aspirin and ibuprofen can pose serious risks to the mother and fetus, including miscarriage.

What the new study found

The new study focused on girls’ reproductive organs and did not examine any links to autism.

Fischer said she wanted to conduct the new research because several experimental animal studies showed that offspring of mothers given acetaminophen during pregnancy had smaller ovaries and fewer eggs. The medication appeared to interfere with egg formation and division in those experiments, Fischer said.

The new study, published this week in the journal Human Reproduction Open, is one of the first to assess human use. The scientists enrolled 685 women in Denmark during the first trimester of pregnancy, a crucial time for fetal development, and evaluated 302 of their baby girls when they were three months old.

The pregnant women logged their acetaminophen use and submitted urine samples so researchers could measure how much of the drug was in their system.

The study found that girls exposed to acetaminophen in the womb had, on average, 40 per cent smaller ovarian volume, 13 per cent smaller uterine volume and 23 per cent fewer ovarian follicles — the structures that contain immature eggs — compared with girls whose mothers did not use acetaminophen during pregnancy. They also showed lower levels of a hormone linked to ovarian reserve.

Smaller ovaries can signal that a person has fewer eggs, which may make it harder to get pregnant. Girls are born with all the eggs they will ever have; the body cannot make more.

Having fewer eggs can also hasten earlier menopause. Early menopause, defined as beginning before age 45, is a health concern because it means a prolonged absence of estrogen, a hormone that protects the brain, bones and heart.

However, this study captured only a snapshot in time; the researchers did not follow the girls long-term to determine future fertility.

In its statement, ACOG noted that the “clinical significance of these findings is uncertain or unknown. The oldest participants evaluated were adolescents, and the study cannot determine whether the observed differences are associated with future reproductive outcomes such as fertility, ovulatory function, reproductive lifespan, or other measures of reproductive health.”

The researchers also analyzed data from 1,210 girls in the Copenhagen Mother-Child Cohort who were followed from infancy to adolescence; their mothers reported paracetamol use during the third trimester.

That data showed that fetal acetaminophen exposure was associated with smaller ovaries during adolescence and smaller uteruses at puberty.

‘The safest drug we have’

Fischer said the new findings shouldn’t stop pregnant women from taking acetaminophen if they need it. More research is needed to determine whether the drug directly caused the reproductive organ changes.

“But on average, we do see a difference between groups, and we do feel concerned about it,” she said.

Many women in the study took acetaminophen for headaches and musculoskeletal pain, Fischer said, and women should weigh alternatives before reaching for an over-the-counter pill.

“I think we really need to have a discussion of why paracetamol is the first thing you grab in your gym bag,” she said. Alternative treatments may help with certain conditions, such as heat for some back pain.

Dr. Christian De Geyter, a retired senior scientist at the University of Basel who studies fertility and reproductive toxicology, wrote in a commentary accompanying the research that the “eminent importance” of the findings “cannot be stressed enough!” He said the “duration and dose must be taken into consideration” and argued that recommendations about the use of acetaminophen should be reversed.

The drug “is still safe, to some extent; take it if you need it, but consider alternatives when possible,” he told CNN. “There are many, many things that can be avoided, rather than just always taking medicine.”

But other experts were more cautious about the new study’s findings and worried it could easily be misinterpreted.

Dr. Gavin Stewart, a senior lecturer in evidence synthesis at Newcastle University, said the study size is small, and because researchers measured many different potential effects, false positive findings could be difficult to distinguish from true effect.

“When you hunt really hard for a pattern, you inevitably find one. I’m worried that the authors are over-interpreting the one they found,” Stewart, who did not work on the new study, told the Science Media Centre.

“I am very concerned that this exploratory study will be misinterpreted. Pregnant women already have a limited choice of pain medication, and paracetamol has an extremely high safety profile. They should not conclude from this study that paracetamol will harm their child,” he said.

While “impressive,” the new study does not show that acetaminophen exposure causes reproductive organ changes, noted Dr. Hugh Taylor, a specialist in obstetrics and gynecology and reproductive endocrinology at Yale School of Medicine.

“What are the other things they took the Tylenol for? Did they have a fever during pregnancy? Was an infection at play, which we know causes congenital defects, as do infectious diseases and high temperatures. So is it really the Tylenol or the reason they took the Tylenol? This study cannot answer that,” said Taylor, who was not involved with the new research.

There are good reasons pregnant people need relief from pain and fever, he said, and “Tylenol is the safest drug we have when it’s needed.”

“We shouldn’t take it like candy,” Taylor added. “But it’s the safest drug to take in pregnancy, and there’s some darn good reasons why you should use it in pregnancy if needed. But like any other drug, take it in moderation.”