Brief exposure to over-the-counter analgesics during the first two trimesters of pregnancy may induce epigenetic changes in fetal germ cells that could reduce fertility for future generations, according to Scottish researchers.
The in vitro and in vivo study of acetaminophen (paracetamol, Tylenol, Johnson & Johnson) and ibuprofen (Advil, Pfizer) exposure in human fetal testis and ovarian tissue showed, among other observations, that germ cell number was significantly reduced following exposure to either analgesic.
The study, led by Rod T Mitchell, MBChB, PhD, of the Medical Research Council Centre for Reproductive Health, at the University of Edinburgh, UK, was published online on April 16 in Environmental Health Perspectives.
These findings reinforce the importance of following clinical guidelines for the use of analgesics during pregnancy, the study authors say.
“We would encourage women to think carefully before taking painkillers in pregnancy and to follow existing guidelines, taking the lowest possible dose for the shortest time possible,” the study authors warn in a statement by the University of Edinburgh.
Growing Evidence of Possible Effects of Analgesics in Pregnancy
In tissue samples taken from fetuses during the first trimester and exposed to therapeutically relevant doses of acetaminophen for 7 days, the number of germ cell gonocytes was reduced by 28% in testes and by 43% in ovaries, Mitchell and colleagues demonstrated. Similarly, exposure to therapeutic levels of ibuprofen resulted in a 22% reduction in gonocyte number in human fetal testes and a 49% reduction in human fetal ovaries.
And after xenografting human testis tissue from a fetus in the second trimester of development into pregnant mice, the researchers found that exposure to acetaminophen or ibuprofen for 7 days significantly reduced total germ cell number compared with control mice treated with vehicle (43% and 54%, respectively).
Even a single day of exposure to acetaminophen followed by 6 days of vehicle led to a 22% reduction in total germ cell number compared with controls. The investigators said they used only fetal testis tissue after being unable to achieve good viability with human fetal ovarian tissue xenografts.
The same effect was observed in animal models, following analgesic exposure in rat fetal testis/ovary cultures, and in fetal testes and ovaries after in vivo exposure in pregnant rats.
This indicates “translatability across experimental models and species,” Mitchell and colleagues suggest.
And changes in germ cell development following exposure to analgesics in pregnancy could also have long-term implications, they point out.
In earlier studies in pregnant rats, the investigators found that a reduction in the number of germ cells following exposure to analgesics triggered DNA changes that affected the fertility of female rat offspring. It also affected the fertility of females in subsequent generations.
This “intergenerational transmission of reproductive effects, including via the paternal line…is indicative of an epigenetic mechanism,” they say.
Although acetaminophen is the most commonly used over-the-counter pain medication worldwide, followed by ibuprofen, there is lack of consensus about its mechanism of action. More recently, concern has been growing about possible adverse effects on reproductive health of these analgesics.
As previously reported by Medscape Medical News, a large metabolomic study has linked acetaminophen use to a depletion of sulfated sex hormones. At the time, the researchers said their findings may indicate that fetal exposure could be linked to increased risk of male urogenital malformation at birth.
And in another recent report, French investigators observed a sharp decrease in the number of germ cells in explants of human fetal ovaries exposed to ibuprofen for short periods. This raises the possibility that daughters born to women who take ibuprofen early in pregnancy could have an insufficient ovarian reserve and subfertility, they suggested. They estimated that more than 25% of pregnant women take ibuprofen.
“Although translation of our results to human pregnancy has to be considered with caution, they add to a growing body of evidence concerning potential effects of analgesics during pregnancy on human developmental outcomes,” Mitchell and colleagues write.
“This, coupled with the high prevalence of analgesic use during pregnancy, suggest that prospective studies to investigate potential effects of analgesic use in pregnancy on outcomes in offspring should be a research priority.”
Patients Shouldn’t Be Frightened, Prospective Research Needed
But clinicians should not yet make any changes to current clinical practice, said Hal Lawrence, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists (ACOG), commenting on the report by Mitchell and colleagues.
“ACOG and ob/gyns across the country have always identified acetaminophen as one of the only safe pain relievers for women during pregnancy, and this latest study does not indicate that there is reason to alter that,” Lawrence told Medscape Medical 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. However, as always, any medication taken during pregnancy should be used only as needed, in moderation, and after the expectant mother has consulted with her doctor.”
Between the late 1990s and mid-2000s, up to 76% of pregnant women in the United States reported using an analgesic at least once during pregnancy, Mitchell and colleagues note. In France, up to 89% of pregnant women said they took a painkiller during the same period of time.
The study was funded by the Medical Research Council, Wellcome Trust, and British Society of Paediatric Endocrinology and Diabetes. The authors and Lawrence have reported no relevant financial relationships.
Environ Health Perspect. Published online April 16, 2018. Full text
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