Prenatal Painkiller Use May Affect Future Fertility Of Unborn

Fetal human tissue exposed to paracetamol and ibuprofen for a week had reduced numbers of germ cells – the cells that develop into sperm and eggs, new research about the potential effects of exposure to painkillers during pregnancy has found.

It would obviously be unethical to subject pregnant women and their unborn babies to potential harms, so the researchers used animals and lab-based research involving fetal human tissue to try to replicate the effects of painkiller exposure during pregnancy.

Researchers said their results “raise concerns” about the use of painkillers during pregnancy, as they could cause the unborn child to have fertility problems. The obvious issue with this study is that it was performed on mice and in tissues grown on dishes in laboratories, so it can’t show us the true effects of painkillers on pregnant women.

It’s also not possible to say whether the effect of the painkillers is reversible, or over what timescale.

Painkillers During Pregnancy

Current guidelines advise that paracetamol is usually safe to take during pregnancy but at the lowest effective dose for the shortest possible time. Ibuprofen should be avoided during pregnancy unless you have been specifically advised to take it by your doctor.

The study was carried out by researchers from the University of Edinburgh and Copenhagen University Hospital.

Researchers stated their results suggested that painkillers have an effect on the level of germ cells, which may alter how DNA is formed and so could potentially affect future generations. But these results came from tests that were not performed in humans, and many other factors that contribute to fertility were also not accounted for.

This was a laboratory study using human tissue exposed to painkillers in a dish, as well as a mouse model, to determine the effect of paracetamol and ibuprofen on the number of germ cells in the reproductive organs.

While this type of laboratory research can provide preliminary data, it does not necessarily translate to what would happen in the human body. It’s also not possible to predict long-term outcomes or link this data to medical conditions.

However, randomised controlled trials on the use of painkillers in pregnant women would be unethical.

The Research Methods

The researchers wanted to test whether painkillers affect levels of fetal germ cells in the reproductive organs. To do this, they performed laboratory experiments in dishes, and tests on mice.

For the studies in dishes, germ cells from the ovaries and testes of first-trimester fetuses were exposed to paracetamol or ibuprofen for 7 days. The fetal tissue samples were obtained from elective terminations of pregnancy, with the written consent of the mothers.

Exposure/treatment regimens and the different investigative models used in the present studies.

Exposure/treatment regimens and the different investigative models used in the present studies. Each panel shows a different experimental model together with the exposure/treatment (colored circles) regimen employed, including timescale.
Credit: Pablo Hurtado-Gonzalez, et al.

For the mice studies, the researchers took germ cells from the testes of second-trimester fetuses and grafted them onto host mice. These were then randomly selected to receive paracetamol for 1 to 7 days, ibuprofen for 7 days or a placebo. These kinds of grafts were used as they have been shown to mimic how the testes grow and function during development in the womb.

The painkillers were delivered to the mice in doses determined to be “human-relevant” based on the UK maximum recommended daily dose of paracetamol (20mg/kg 3 times a day) or ibuprofen (10mg/kg 3 times a day).

The Results

In the laboratory studies using human tissue grown on dishes:

  • using testis cells, the number of germ cells was reduced by 28% when exposed to paracetamol and by 22% when exposed to ibuprofen
  • using ovary tissue, the number of germ cells was reduced by 43% when exposed to paracetamol and by 49% when exposed to ibuprofen

In the experiments using germ cells grafted onto mice:

  • after 7 days of medication, the number of germ cells had reduced by 43% for paracetamol and by 53% for ibuprofen
  • after 1 day of paracetamol, the number of germ cells had reduced by 22%

The researchers said that, under experimental conditions, exposure to human-therapeutically relevant levels of paracetamol and ibuprofen caused significant reductions in the number of germ cells in human fetal testes and ovaries.

Conclusions

The study found that taking regular paracetamol and ibuprofen for 7 days reduced numbers of germ cells – the cells that develop into sperm and eggs. However, this type of laboratory research has limitations. In particular:

  • graft testicular and ovary tissue may not respond in exactly the same way as normal reproductive organs do in the womb
  • the grafts were only fragments of the reproductive organs – the whole organ might act differently
  • it’s not possible to tell whether exposure to painkillers in pregnancy would have any detrimental effects on the child in terms of the development of their sexual characteristics or future fertility.

Current guidelines do not advise against the use of paracetamol in pregnancy, although they recommend it be used at the lowest possible dose for the shortest possible time.

However, the guidelines do say ibuprofen should be avoided during pregnancy, unless it’s taken on the explicit advice of a doctor.

The work was funded by the UK Medical Research Council, the Wellcome Trust, and a British Society of Paediatric Endocrinology and Diabetes Research Award.

Pablo Hurtado-Gonzalez, Richard A. Anderson, Joni Macdonald, Sander van den Driesche, Karen Kilcoyne, Anne Jørgensen, Chris McKinnell, Sheila Macpherson, Richard M. Sharpe, and Rod T. Mitchell
Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems
Environ Health Perspect; DOI:10.1289/EHP2307

Top Image: Chris Nurse, Wellcome Images