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In a comprehensive new study, Professor David Møbjerg Kristensen from Roskilde University and Rigshospitalet, together with colleagues from Denmark and France, has shown that the painkiller paracetamol may pose a risk to the fertilized egg in the very first days after conception. The results have been published in the renowned journal Human Reproduction.

If a woman has taken painkillers such as Panodil, Pinex, or Pamol around the time of conception, it may mean that the fertilized egg, the embryo, does not divide as it should and may even perish. The researchers have demonstrated how paracetamol interferes with the copying of DNA before the cell divides, by blocking the enzyme that reads the old DNA strand and creates the new one. This can therefore have fatal consequences in the first six to seven days after fertilization, when the egg needs divide and mature before it finds its way into the uterus and implants.

The research could have implications for a large number of women. Somewhere between 10 and 40 percent of all women lose the embryo in the first week after fertilization. Around half of these cases are due to mutations; while smoking and alcohol are also considered to play a role. 

Now, the researchers behind the new study believe that paracetamol may also be a contributing factor. Danes in particular hold the Nordic record for painkiller consumption. Every year, we consume about one billion painkillers—equivalent to around 500 tons—just from pharmacies. On top of that come pills purchased in kiosks and supermarkets.

 

10 Questions for the professor about paracetamol and pregnancy 

1. What do you personally find the most exciting about this study?

- I find it deeply fascinating that we have discovered this mechanism, where paracetamol penetrates the fertilized egg and blocks something absolutely essential—DNA synthesis, that is, the actual copying of DNA right before cell division. This is the very blueprint for how our body is built. And we can then link this mechanism, in terms of timing, to disturbances of the embryonic development in the very first days after fertilization, when we likely see some of the most critical cell divisions in the entire development.

2. Why are the first days after fertilization such a critical period?

- The first DNA copies and cell divisions are absolutely crucial for the fertilized egg to mature in the right way, so it can reach the uterus and implant there.

3. Why did you specifically choose to study the fertilized egg in this project?

- The idea grew out of another study we conducted together with my French colleagues from Inserm, the French National Institute of Health and Medical Research. In that study, we examined the effects of paracetamol during pregnancy in mice on the development of eggs in the ovaries of their daughters. Just as in women, eggs in mice are formed during fetal development, and no new ones are produced later. 

We observed that the adult daughters had only about half as many eggs as the female mice in the control group. This has since also been confirmed by other research groups. We also found a possible explanation: paracetamol appeared to slow down the division of the stem cells that form the ovaries. 

This raised the questions: does paracetamol actually stop cell division in the fetus? And if so, how does paracetamol affect the early embryonic development, where we know that every single cell division is of extreme importance? Luckily, we received support from �鶹�� to investigate this further.

4. You have worked with embryos and tissue from both mice and humans, but also with yeast. Why yeast?

- Yeast is a fantastic model for the cell. It is a very simple cell and easy to work with. The fact that we can demonstrate this mechanism in yeast supports our argument that paracetamol interferes with something fundamental in how life functions.

5. It is a very thorough study, but as a researcher there are always reservations to consider. What is the most important one here?

- An important reservation is that we will never obtain definitive proof of what happens inside a woman’s uterus. For ethical reasons, we can never conduct a randomized trial where 25 women trying to conceive are given paracetamol and 25 are given a placebo, i.e. sugar pills. So we won’t get the final proof, or what one might call “the smoking gun.” But we can put the puzzle together all the way around the missing piece.

Some of the pieces have been placed already—by us and by other researchers in earlier studies—and now we also have a piece with this mechanism and its effect on the fertilized egg, which we have demonstrated in the laboratory.

Another piece is our finding that the concentrations of paracetamol we detect in women after a standard dose of one gram of painkillers are the same concentrations that, in the lab, damage embryonic development and block cell division.hovedpinemedicinen på et gram, er de samme koncentrationer, som i laboratoriet skader fosteranlægget og blokerer for celledelingen.

6. What considerations have you made about the fact that these results could cause anxiety among women who want to become pregnant – or who are already pregnant?

- On the one hand, we put a lot of effort into communicating our results in a nuanced way, precisely to avoid creating unnecessary worry.

On the other hand, we have known for years—and it has also been shown in studies—that many people do not regard these painkillers as real medicine with side effects, since they can buy them alongside chewing gum and chocolate in the supermarket. So we also want to raise awareness about this, and encourage more people to reflect on their use of painkillers.

7. What would you say to the woman reading this who wants to become pregnant?

- That she should not be worried, and if she still is, she should talk to her doctor. Because this is not about never being able to take paracetamol, but about treating it with the same common sense as with any other medicine—and being especially mindful in connection with pregnancy.

8. You have been researching paracetamol for nearly 20 years – why is it so important to keep digging deeper?

- In addition to my position as a professor at Roskilde University, I am part of a research group at Rigshospitalet in the Department of Growth and Reproduction, which has for many years studied the relationship between our fertility and the chemical substances in our environment. 

And 15 years ago, we showed that paracetamol, like a number of environmentally harmful substances, has endocrine-disrupting effects, and can, among other things, inhibit the formation of the male sex hormone testosterone in the fetus. That’s where the interest started. Since then, in experiments with the substance, I have observed changes in our test animals and their offspring, including damage to the ovaries, changes in the positioning of the sex organs in newborn male rats and mice, and in newborn boys we have seen that the testicles have not descended into the scrotum. This has driven me and my group, because we knew there was something here that was entirely new—and probably not entirely good.

9. What kind of impact would you like your research to have?

- Personally, I would like painkillers to only be sold in pharmacies, but of course, I am likely influenced by my many years of work with these substances. But if we can simply achieve that more people reflect on their consumption and recognize that paracetamol is real medicine with real side effects, then we will have come quite a long way.

10. How do you follow up on this study?

- We have received a grant from the Independent Research Fund Denmark to follow pregnant women who have undergone fertility treatment. We know the exact date of fertilization and can see in their blood samples whether they took paracetamol around the time they became pregnant. Then we will investigate whether the concentration of paracetamol in the blood can be linked to a higher risk of embryo loss. That is the statistical part we are examining here.

And we are also working on taking our data from this new study and trying to understand it in relation to brain development. A series of studies from Denmark, Norway, and the USA suggest that there may be a connection between paracetamol use during pregnancy and, for example, ADHD in children. We are investigating whether the mechanism we have now identified can help explain the development of ADHD during the brain’s growth spurt late in pregnancy. My group and I are fortunate to have received an Ascending Investigator grant from �鶹�� for this study, which we are conducting together with colleagues from Gentofte and Glostrup in the COPSYCH cohort, as well as from Harvard Medical School and Harvard School of Public Health in Boston. We started last year, and the study will run over four years.