Paracetamol Use During Pregnancy-A Call for Precautionary Action

Paracetamol, otherwise known as acetaminophen, is the active ingredient in over 600 prescription and nonprescription analgesic and antipyretic medications. Worldwide and in the United States, more than 50% and 65% of pregnant women use acetaminophen, respectively. Currently, acetaminophen is considered to be of minimal risk and appropriate for use during pregnancy by the US Food and Drug Administration and European Medicines Agency. Despite this, there exists concern that environmental exposure to pharmaceuticals including acetaminophen during fetal life may contribute to the increased rates of neurological, urogenital, and reproductive disorders. This consensus statement aimed to provide an evidence-based summary of the literature relating to neurological, urogenital, and reproductive outcomes that have been associated with maternal and perinatal use of acetaminophen. This consensus statement was created by an international multidisciplinary group consisting of experts in neurology, obstetrics/gynecologists, pediatrics, epidemiology, toxicology, endocrinology, reproductive medicine, and neurodevelopment. A literature review was conducted for studies published between 1995 and 2020, including only those with acetaminophen as an independent exposure. There is a limitation in the existing epidemiological literature addressing these questions, and future efforts are required. One concern about the effects of acetaminophen on pregnancy is its action as an endocrine disruptor and potential to interfere with the activity of endogenous hormones essential for healthy fetal development. In vivo, in vitro, and ex vivo studies demonstrate that acetaminophen perturbs hormone-dependent processes such as inhibiting androgen production, increasing estrogen production, disrupting steroidogenesis, depleting sulfated sex hormones, altering immune function, inducing oxidative stress, and indirect activation of the endocannabinoid system. Epidemiologic evidence examining prenatal acetaminophen exposure in over 130,000 mother-child pairs has shown an association with male urogenital and reproductive tract abnormalities. Experimental evidence in rodents and human cell lines shows that both acute and long-term exposures to acetaminophen result in reduction in fetal androgens and may reduce primordial germ cells, increasing risk of early-onset ovarian insufficiency. Epidemiologic evidence examining prenatal acetaminophen exposure in over 220,000 mother-child pairs has shown an association with a range of clinically assessed and parent-reported neurodevelopmental outcomes, primarily but not limited to behavioral abnormalities including attention-deficit/hyperactivity disorder (ADHD). Of the 19 observational studies investigating dose-response, 16 found a dose-response association where duration of exposure was associated with increased risk. Experimental animal studies show that perinatal acetaminophen exposure increases the risk of brain and behavioral abnormalities in rodents, and that the strongest effects of long-term use and exposure occur at a time equivalent to the beginning of the third trimester and the time around birth. This consensus statement and systematic review finds evidence of significant neurodevelopmental and reproductive adverse effects of acetaminophen prenatal exposure, particularly with long-term use. It is recommended by this document that acetaminophen be used by pregnant women cautiously at the lowest effective dose for the shortest possible time and longer or higher-dose use be discussed with a health professional. It is also advised that packaging display warning labels related to the evidence discussed here.