Acetaminophen use during pregnancy requires a broader safety evaluation beyond neurodevelopmental outcomes, and its analgesic efficacy should be interpreted in the context of nociceptive pain rather than pain in general.

Abstract Most organizations, including the World Health Organization (WHO), consider the causal relationship between acetaminophen use and neurodevelopmental outcomes to be unclear or unconfirmed, whereas the U.S. Food and Drug Administration (FDA) recommends that clinicians exercise caution based on clinical judgment. Guidelines generally continue to recommend acetaminophen as a first-line pharmacological option for fever and pain when medically indicated, at recommended doses and for the shortest duration. Beyond neurodevelopmental outcomes, other adverse perinatal and postnatal outcomes—such as altered male anogenital distance, asthma, lower intelligence quotient, low birth weight, preterm birth, stillbirth, low Apgar scores, childhood obesity, and reduced academic performance—have also been reported, though causality remains uncertain. When evaluating the safety of acetaminophen, it may be preferable to consider the broader range of available evidence rather than focusing solely on neurodevelopmental outcomes. Acetaminophen is widely used as a first-line pharmacological option for nociceptive pain (NcP), whereas its efficacy for neuropathic/nociplastic pain (NeP/NpP) appears limited based on currently available evidence. Taken together, these considerations suggest that routine initiation of acetaminophen therapy may not consistently provide clinically meaningful benefit when NeP/NpP is suspected, given the limited evidence of efficacy in these conditions. If no meaningful pain reduction is observed after a reasonable trial period of acetaminophen therapy, referral to a pain specialist may be considered. Although no clear evidence defines the optimal duration of such a trial, approximately 1 week may represent a practical reassessment interval. When pain characteristics suggest the possible presence of NeP/NpP, prompt referral to a pain specialist may be considered rather than initiating empirical acetaminophen therapy. Indications such as fever and pain, as described in several professional and regulatory statements, may contribute to ambiguity in clinical interpretation, particularly in contexts where formal pain classification is not explicitly applied. The available evidence suggests that acetaminophen is widely regarded as a first-line pharmacological option for fever and is commonly used for NcP during pregnancy, while its efficacy in NeP/NpP appears limited.