Disorders appearing in young adulthood risked by low testosterone include low sperm counts and testicular germ cell cancer.
The risks of low testosterone in male fetuses cited by the study authors include common male reproductive disorders that manifest at birth, such as an undescended testis (cryptorchidism) and the defect known as hypospadias, a urethral malformation that results in the boy's urine outlet not being in the normal position at the end of the penis.
Disorders appearing in young adulthood also risked by low testosterone include low sperm counts and testicular germ cell cancer.
One of the authors, consultant pediatric endocrinologist Dr. Rod Mitchell, a Wellcome Trust intermediate clinical research fellow at the UK's University of Edinburgh, says:
"This study adds to existing evidence that prolonged use of acetaminophen in pregnancy may increase the risk of reproductive disorders in male babies." His advice for expectant women is:
"We would advise that pregnant women should follow current guidance that the painkiller be taken at the lowest effective dose for the shortest possible time."
The study, conducted by Dr. Sander van den Driesche and colleagues at the University of Edinburgh, has been published in Science Translational Medicine, a journal of the American Association for the Advancement of Science.
Mice with human testes
To examine the effects of acetaminophen, also known as paracetamol, on testosterone production, the researchers used a xenograft model in which fragments of human fetal testes were transplanted into castrated mice.
To overcome the limitations of ordinary animal testing, as well as the obvious problems that would be encountered by trying to take measures of testosterone production in unborn boys and link these with drug exposure in pregnant women, the team used a xenograft technique they had developed and validated as a model of human fetal testicular development.
The xenograft model "reflects physiological development and can be used to test the effects of chemical exposures on testosterone production."
In the grafted mice treated 3 times a day for 7 days with a human-equivalent dose of acetaminophen (20 mg per kg of bodyweight):
- Testosterone levels in the blood dropped by 45%
- The weight of the seminal vesicle glands fell by 18%.
The seminal vesicles secrete the large part of the semen fluid, and the researchers used their weight as a biomarker of exposure to testosterone. The results are percentage drops compared with no acetaminophen in a placebo treatment.
Exposure to the drug - available over the counter to women in the US under brands including Tylenol - for a single day, however, did not affect these measures of testosterone production.
The researchers point out that while it is too early to call how applicable these lab findings are with regard to human use of the analgesic, "the findings caution against extended use of acetaminophen during pregnancy."
The team, from the MRC Centre for Reproductive Health at the university, say further research would be needed to understand how acetaminophen could be having the effect on testosterone production in male fetuses.
The human fetal testis tissue used in the medical research was donated by women who had undergone pregnancy termination.
The laboratory research is a more direct examination of acetaminophen effects on fetal testicular tissue, to build on links in previous studies cited by the authors between prolonged use of the painkiller during pregnancy and an increased occurrence of, for example, undescended testes in boys.
'Short-term treatment of fever outweighs potential risk'
The UK's Royal College of Paediatrics and Child Health has responded to the study with a reminder that pregnant women should consult a doctor when seeking treatment of pain or fever.
Dr. Martin Ward-Platt says on behalf of the college that the study is a clear message about expectant mothers not taking prolonged acetaminophen, and keeping to such medical guidance.
The US Food and Drug Administration says: "Pregnant women should always consult with their health care professional before taking any prescription or over-the-counter medicine."
Dr. Ward-Platt adds that the study specifically relates to acetaminophen/paracetamol use over at least several days, but that "there are times where one or two doses is needed to treat one-off episodes of fever for example."
"Fever during pregnancy can be harmful to the developing embryo, with links to a significant increase in the rates of spina bifida and heart malformations, so small doses of paracetamol are sometimes necessary."
Dr. Ward-Platt concludes: "My message to expectant mothers is clear - avoid overuse of paracetamol, but if you do have a fever, or any other sort of pain where you would normally use paracetamol, seek medical advice."