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Paracetamol use during pregnancy can impair the fertility of sons

A new, meticulously conducted experimental study by scientists at the University of Edinburgh has discovered that the pain reliever paracetamol can suppress the production of the male sex hormone testosterone during pregnancy. This reduction can be detectable even after paracetamol has been used for more than seven days during pregnancy. A single day of use does not lead to any detectable changes, and the period between two and six days has not been studied. Testosterone is a key hormone for the development of the sex organs in male embryos. This study provides further evidence of the serious effects that paracetamol, when taken during pregnancy, can have on the lifelong development of offspring.

As early as 2011, an epidemiological study pointed to a significantly increased risk of developing cryptorchidism (undescended testicles) in boys. Current US studies show that up to six percent of newborn boys are affected by cryptorchidism. Affected children may later experience reduced fertility and an increased risk of developing malignant testicular tumors. Sperm count and sperm viability may also be reduced later in life. The combined use of two painkillers by pregnant women was associated with a sevenfold increased rate of cryptorchidism in newborn boys. This study raised the suspicion that the effects of even a single 500 mg acetaminophen tablet could be more harmful to the unborn child than the ten most common environmental pollutants. However, the study has been criticized for not definitively establishing a causal link.

This criticism has now been addressed by the current study from Edinburgh, which has analyzed the mechanisms in detail. To elucidate the link between paracetamol use during pregnancy and its impact on the fertility of the children, an experimental approach was employed that closely mimics the conditions during human pregnancy. Mice were implanted with human testicular tissue. The mice were then administered paracetamol at standard therapeutic doses for seven days.

Professor Hartmut Göbel, head physician of the Kiel Pain Clinic, emphasizes the high significance and generalizability of the data: “The study investigates the possible mechanisms by which paracetamol disrupts the fetal development of sex hormones. For the first time, it elucidates how paracetamol interferes with male sex hormones during the development of the sex organs in the womb in male fetuses. Particularly significant is the fact that the paracetamol concentrations in the study were no higher than those normally used therapeutically in humans for everyday pain.”.

Mice treated with paracetamol showed significantly lower levels of testosterone in their blood than mice treated with a placebo. However, when mice were treated with paracetamol for only one day, no significant effect on testosterone production was observed.

The study's lead author, Dr. Rod Mitchell, commented: "This study adds further evidence to the existing knowledge that prolonged use of paracetamol during pregnancy increases the risk of fertility problems in male babies. We therefore recommend that pregnant women take painkillers in the lowest possible dose."

Most male infertility disorders are related to reduced testosterone production during the embryonic and fetal stages before birth. However, the factors that cause this reduction in testosterone production in utero are largely unknown. Epidemiological studies have shown that exposure of unborn children to paracetamol during pregnancy is associated with an increased risk of undescended testicles, subsequent testicular cancer, and infertility. It was unclear, however, whether paracetamol could directly reduce testosterone production during the fetal stage. This study investigated whether paracetamol could alter testosterone production in human fetal testicular tissue. Exposure to therapeutic doses of paracetamol for seven days resulted in a significant reduction in testosterone levels of 45%. Testicular weight also decreased significantly by 18%. Further studies in rats showed that the paracetamol-induced reduction in testosterone is caused by reduced expression of key steroids that are enzymes required for testosterone synthesis.

Professor Hartmut Göbel is concerned about the long-term effects of even short-term paracetamol use during pregnancy: "The study uses a very carefully conducted experimental model to illustrate why paracetamol taken during pregnancy can lead to undescended testicles and testicular atrophy. Even seven days of use can have lifelong effects on fertility.".

The scientists point out that the findings cannot be directly extrapolated to humans. However, corresponding studies cannot be conducted on pregnant women for ethical reasons. Therefore, it is not possible to scientifically analyze direct evidence of the connection in pregnant women. The study results are particularly important if paracetamol is taken over a longer period or repeatedly and episodically during pregnancy. Previous studies have already shown an effect between the pain-relieving properties of paracetamol and testosterone. A study from 1985 described how treatment with testosterone reduced the effect of paracetamol by approximately half. Another study from 2012 also described a reduction in testosterone after just three days of pretreatment with paracetamol, acetylsalicylic acid, or indomethacin in fetal testicular tissue of rats. Two further studies from 2013 (a , b) also point to this connection.

Prof. Hartmut Göbel: “Even today, paracetamol is recommended almost without reservation in many guidelines as a pain reliever for pregnant women. Current guidelines and recommendations even state that paracetamol can be taken at any time during pregnancy. It is frequently used, especially for episodic, recurring headaches such as tension headaches, migraines, or headaches associated with infections. Paracetamol is one of the most frequently used medications, particularly through self-medication in Germany. Epidemiological studies show that over half of pregnant women resort to paracetamol even for minor pain due to indiscriminate treatment recommendations. However, studies have demonstrated that, despite the significant risks to the children's lives, paracetamol is no more effective than a placebo for back and muscle pain. Numerous alternatives exist for headaches. Given the extensive data available, paracetamol can no longer be recommended during pregnancy, and certainly not without reservation. Pain during pregnancy should always be treated only after consulting a doctor.” "Medication should only be used if absolutely necessary.".

Pregnant women should be informed about the new study results. They should be able to make an informed and active decision as to whether, based on this data, paracetamol can be responsibly used to treat headaches or backaches. Pain relievers, especially during pregnancy, should only be taken in the lowest effective dose for the shortest possible time and only on the advice of a doctor.

Prof. Hartmut Göbel emphasizes the risks, especially for boys: "Mothers expecting a son as a baby should be particularly cautious about taking paracetamol during pregnancy.".

Extensive international epidemiological studies have previously strengthened suspicions that taking paracetamol during pregnancy increases the risk of children developing asthma later in life. These studies demonstrate that paracetamol affects the development of fetal liver stem cells, which are crucial for the development of the immune system. Disruption of these cells can negatively impact the immune response later in life. This mechanism may explain why children whose mothers took paracetamol during pregnancy are more likely to suffer from allergies and asthma later on.

However, according to recent studies, paracetamol use during pregnancy also increases the risk of severe developmental disorders, attention deficit hyperactivity disorder (ADHD), and hyperactivity syndrome (HAD) in children. Children exposed to paracetamol before birth show substantial neurodevelopmental impairment three years after birth.

Epidemiological studies from Denmark show that more than half of all mothers report using paracetamol during pregnancy. Children of mothers who used paracetamol during pregnancy showed a 1.37-fold increased risk of being hospitalized with a hyperkinetic disorder. Given the high prevalence of paracetamol use during pregnancy, these findings are highly relevant to society and require careful attention in the care of pregnant women and children.

In Germany, the product information for paracetamol still fails to mention its potential fetotoxicity, as the German Medical Journal (Deutsches Ärzteblatt) notes. Despite clear indications of this for several years, the product information states that epidemiological data on the oral use of therapeutic doses of paracetamol have shown "no evidence of possible adverse effects on pregnancy or the health of the fetus/newborn." Pregnant women are not being adequately informed. Even the Embryotox encourages its use.

Paracetamol is approved for the "symptomatic treatment of mild to moderate pain and fever." It has no place in the treatment of severe and very severe pain. The drug is neither approved for this purpose, nor have its efficacy, tolerability, and safety been established. The argument that paracetamol is the only option for very severe pain because severe pain in the mother is harmful to the unborn child lacks a sound scientific basis and contradicts its approved indications. The drug does not alleviate severe and very severe pain; therefore, attempts are made to achieve an effect through higher doses and repeated administration based on its supposed "safety." The therapeutic goal is still not achieved. In addition to the continued pain, the mother and unborn child are further burdened by the drug's effects.

Pain specialists almost never use paracetamol; it is effective at best for mild to moderate pain, but not for moderate or severe pain. Paracetamol is no more effective than externally applied peppermint oil for tension headaches. It does not alleviate severe migraine attacks. It is not superior to a placebo for back and muscle pain. Therefore, it has no place in pregnancy for moderate or severe pain; the only previous justification for its use in mild pain was its perceived "safety." However, current studies on the increased risk of asthma, ADHD, and undescended testicles have refuted this claim. Women should be able to make informed decisions about their treatment.

And there are numerous other options. Mild pain during pregnancy should be treated with rest, withdrawal, relief, and relaxation. There's no need to swallow 4 grams of paracetamol and try to function only to realize it doesn't help. Back pain can be treated with heat therapy, exercise, and physiotherapy. Obtaining a sick note or a work ban in cases of severe pain can provide relief. Preventive magnesium supplements or magnesium infusions during an attack can also be helpful. Numerous preventive behavioral medicine measures are available. Painkillers should not be taken in early pregnancy. Ibuprofen is an option in the second trimester. Studies have shown that it does not pose an increased risk like paracetamol. For the most severe migraine attacks, sumatriptan is a possible option. Different rules apply in medical emergencies; this section focuses on everyday situations in pain management.

It is absolutely essential that women who require pain relief during pregnancy are clearly informed about the currently known potential risks. They should ask themselves the following questions before using any medication: Do I want my child to be harmed by taking a mild painkiller?

  • Does it increase the risk of infertility?
  • who develops an increased risk of allergies and asthma?
  • an increased risk of poorer overall motor development, impaired communication and social behavior, and increased hyperactivity?
  • increases the risk of hyperkinetic disorders (HKS) and attention/hyperactivity disorders (ADHD)?

Conclusion

If even one of these questions is answered with "no", the decision will be made in favor of the well-being of the unborn child, even in cases of doubt.

Source:

S van den Driesche, J Macdonald, RA Anderson, ZC Johnston, T Chetty, LB Smith, C McKinnell, A Dean, NZ Homer, A Jorgensen, ME Camacho-Moll, RM Sharpe, RT Mitchell, Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model. Sci. Transl. Med. 7, 288ra80 (2015).

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