Free special edition 2023

ADVERSE EFFECTS

Paracetamol, pregnancy and urogenital endocrine disruption: inconclusive studies

● Prompted by observations in animal studies, about a dozen epidemiological studies have inves tigated the possibility that in-utero exposure to paracetamol has an endocrine-disrupting effect on the urogenital system. ● The quality of the evidence provided by these studies is weakened by theirmanymethodological limitations, related in particular to the method used to collect drug exposure data, or failure to analyse the cases of cryptorchidism that required surgical correction. The results on hypospadias in boys exposed to paracetamol in utero are no more robust. ● Among the other drugs available to alleviate fever or pain, nonsteroidal anti-inflammatory drugs (NSAIDs) pose a known risk of serious adverse effects in the unborn child. Opioids can provoke hypogonadism in adults, but this effect has not been demonstrated in children exposed to opioids in utero. ● In practice, during pregnancy, paracetamol remains the analgesic with the best harm-benefit balance, despite its limitations. Given the uncer tainty concerning the possible long-term effects of in-utero exposure to paracetamol , it makes sense to use it selectively, without trivialising its use in pregnancy. P aracetamol is the drug of choice for occasional use to treat fever or mild to moderate pain, including during pregnancy (1). Its main adverse effect is serious liver injury in the event of an overdose (1). It was long thought to present no particular dangers in pregnancy (2). However, in late pregnancy, paracetamol is a risk factor for premature closure of the ductus arteriosus (3). And effects on the neuropsycho logical development of children exposed to paracetamol in utero, especially with high doses, have not been ruled out (4). In the early 2010s, a few animal studies produced conflicting results concerning a risk of testicular disorders. Two cohort studies, including a total of almost 49 000 boys, found no particular risk of persistent cryptorchidism following in-utero exposure to paracetamol ; cryptorchidism (undescended

testes) is described as persistent when surgery would be re quired to correct it. A case-control study demonstrated a link with cryptorchidism in a subgroup of boys exposed to para cetamol in utero for more than 15 days, but did not specify whether the affected boys had persistent cryptorchidism (2). Is more known about the urogenital development of children exposed to paracetamol in utero as of 2022, and the risk of hypospadias or cryptorchidism in particular? This article reviews the main data identified through our lit erature search. In male and female animals: effects on the re productive system. Our 2012 reviewmentioned 5 studies in which high (but unspecified) doses of paracetamol , admin istered orally to animals, reduced testosterone production and spermatogenesis, and caused testicular atrophy (2). Since that review, about a dozen studies in rats and mice have been pub lished on the effects of paracetamol on the progeny of exposed gravid females. Reduced ovarian reserve and fertility were observed in female progeny, even at doses that were not toxic to the gravid females (5,6). Observations in animals cannot always be extrapolated to humans. However, these studies served as a warning of para cetamol ’s potential endocrine-disrupting effects on the uro genital system, prompting epidemiological studies to be conducted (7-9). About a dozen epidemiological studies: mostly negative results. Since 2012, 3 cohort studies and 3 case-control studies have investigated the potential link between in-utero exposure to paracetamol and cryptorchidism or hypospadias (10-15). Cryptorchidismwas primarily evaluated in 3 cohort studies, in a total of almost 80 000 boys (10-12). As in our previous review, the definitions and diagnostic criteria used for cryptorchidism varied. The published results did not distinguish between the risk of cryptorchidismobserved at birth and cryptorchidism present after the first months of life (2). In one cohort study, including a total of 3000 boys, the risk of cryptorchidismwas about twice as high in boys exposed to paracetamol in utero (about 10% to 20%, depending on the period of pregnancy) than in unexposed boys (10). No link was demonstrated in the other two cohort studies and one case-­ control study (11-13).

Excerpt from Prescrire Int April 2023 Full article (2 pages) available to subscribers at english.prescrire.org

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