Paracetamol use during pregnancy - a call for precautionary action

Abstract

Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe.

Fig. 1. Associations between prenatal APAP exposure, reproductive and neurobehavioural development suggested from observational human studies.

Human observational studies suggest prenatal N-acetyl-p-aminophenol (APAP) exposure might be associated with both reproductive and neurobehavioural abnormalities in both sexes. APAP exposure during pregnancy might increase risk of male urogenital and reproductive tract abnormalities, as studies have found an elevated risk of undescended testicles (cryptorchidism) and reduced distance between the anus and the base of the penis, a measure known as the anogenital distance (AGD). Both reduced AGD and cryptorchidism are indicators of disturbed masculinization and risk factors for reproductive disorders in later life. Prenatal APAP exposure has also been associated with earlier female pubertal development. Additionally, epidemiological studies consistently suggest prenatal APAP exposure might increase the risk of adverse neurodevelopmental and behavioural outcomes, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, language delay (in girls) and decreased intelligence quotient. Collectively, the studies suggest that the timing and duration of maternal APAP use are critical factors.

Fig. 2. Evidence of APAP disruption of reproductive and neurological development from animal studies.

In vivo, in vitro and ex vivo studies have shown that N-acetyl-p-aminophenol (APAP) directly perturbs hormone-dependent processes, which leads to disrupted reproductive development and neurodevelopment in both sexes. Fetal exposure in rodents has been shown experimentally to cause reproductive disorders of the male urogenital tract, including abnormalities in testicular function, sperm abnormalities and sexual behaviour. Experiments have shown disruption of female ovarian development resulting in reduced oocyte number and subsequent early ovarian insufficiency and subsequent reduced fertility. Fetal APAP exposure has been demonstrated to induce changes in neurotransmission in the brain manifesting in altered cognitive function, behaviour and locomotion. The studies have shown that the effect of APAP is dependent on the timing of exposure in relation to specific developmental processes and duration as well as dose. AGD, anogenital distance.