Acetaminophen in Pregnancy is Probably Safe, but No One Really Knows for Sure

Figure: Acetaminophen, pregnancy, APAP, painFigureImagine a patient sitting before you who is 14 weeks pregnant. She has a cough, body aches, tachycardia to the 130s, and a fever of 103.5°F. She is also positive for influenza A. The nurse wants to give her acetaminophen. Is that a good idea? This is a surprisingly challenging question! I'll cut to the chase and agree with the U.S. Food and Drug Administration: It's probably safe. In fact, refusing to provide acetaminophen to a pregnant woman with a fever because of “safety concerns” is highly likely to blow up in your face, so don't do that. That said, anyone who delves into this question—should a pregnant woman ever take acetaminophen?—ought to be filled with fear and humility over how little we know. Observational studies have reported associations between acetaminophen exposure in utero and the downstream development of everything from childhood obesity to asthma and ADHD. (Obesity [Silver Spring]. 2019;27[8]:1314; https://tinyurl.com/yc2vfpns; J Allergy Clin Immunol. 2019;144[6]:1534; https://tinyurl.com/3rravjk2; Pediatrics. 2017;140[5]:e20163840; https://tinyurl.com/5n8m6d7x.) Those who believe acetaminophen causes these problems suggest it interferes with prostaglandins, those lipid compounds found throughout the body that are crucial to gonadal and brain development, among other things. (Acetaminophen, while still something of a mystery, has long been hypothesized to work by interfering with prostaglandin function.) Association is not Causation Animal studies have added to the concerns. Researchers in Wuhan, China, fed acetaminophen to hundreds of pregnant mice, and reported that it “induced marked pathological alterations in the fetal hippocampus, bone, kidney, and cartilage.” (Ecotoxicol Environ Saf. 2024:283:116980; https://tinyurl.com/muyvaz9a.) That sounds terrifying until a closer read reveals that these poor mice were given 100 mg to 400 mg per kilogram. So, they were overdosed. The higher-end doses used in the study for an average 70 kg human are equivalent to 56 tablets of extra-strength acetaminophen—an entire bottle! Meanwhile, association is not causation. Acetaminophen exposure and a developmental disorder might each result from some third confounding issue. To illustrate this, consider that a woman with an uneventful pregnancy might take no acetaminophen. But another who has daily body aches from rheumatoid arthritis, is tormented by hyperemesis gravidarum, and develops preeclampsia, a UTI, and a COVID-19 course will probably get some acetaminophen along the way. If her illnesses cause harm to her fetus, this will flag in the data as an “association with acetaminophen.” An excellent study cleverly addressed this. (JAMA. 2024;331[14]:1205.) Using a Swedish national database, the researchers looked at 2.5 million children born from 1995 to 2019, and found that those who were never exposed to acetaminophen in utero had slightly lower rates of neurodevelopmental disorders by age 10 than those who were exposed, including autism (1.33% vs. 1.53%), ADHD (2.46% vs. 2.87%) and intellectual disability (0.70% vs. 0.82%). It sounds concerning, right? But the researchers also did a sibling control analysis comparing biological siblings for concordant or discordant acetaminophen use during pregnancy. No association persisted between acetaminophen use and neurodevelopmental disorders with a sibling as a control. How Little We Know A randomized controlled trial could settle this. It would have to include tens of thousands of patients to detect the hypothesized, exceedingly rare adverse events. It's arguably worth the effort. Consider that N-acetyl-para-aminophenol (variously referred to as APAP, acetaminophen, and paracetamol) is the most widely used medication in the world; it is used in the majority of U.S. pregnancies (65%) and in about half of worldwide pregnancies, and this is so even when we still don't have any definitive idea of how it works. That's right: Everyone uses it. No one really knows how it works. And some researchers assert its use in pregnancy might cause baby boys to have undescended testicles and decreased sperm counts, baby girls to have delayed language skills, and all children to become wheezing asthmatics with lower IQ scores. (Nat Rev Endocrinol. 2021;17[12]:757; https://tinyurl.com/yc8buyad.) The Acetaminophen RCTs Some randomized trials do look at acetaminophen. Most focus on its efficacy as a pain medication. A nice study from Oslo compared ibuprofen 400 mg, 600 mg, and 800 mg with acetaminophen 500 mg, 1000 mg, and 1000 mg plus codeine. Big picture: They were all roughly comparable in pain relief. (Eur J Clin Pharmacol. 2021;77[12]:1843; https://tinyurl.com/3jcnzeb7.) It's partly based on this study that my go-to dose of ibuprofen is 400 mg because pain relief—but not side effects—seems to plateau here. The same study of 350 post-operative patients also found little difference with escalating acetaminophen doses. But I heard somewhere else—probably from the marketing and research behind IV acetaminophen (Ofirmev)—that 1 g is “the pain dose.” So, I tend to give 1 g of acetaminophen for pain and lower doses for fever. I might revisit that now. We're always learning. Other randomized trials—152 post-tonsillectomy children from New Zealand or 547 adults with minor musculoskeletal traumas from the Netherlands—also found little difference in pain relief between acetaminophen and NSAIDs. (Can J Anaesth. 2013;60[12]:1180; https://tinyurl.com/ksvsu8wb; Ann Emerg Med. 2018;71[3]:357.) But these are all small, simple studies: 350 patients, 152 patients, 547 patients being asked about pain shortly after receiving a medication. Who will organize the study that randomizes 100,000 patients and then, years later, asks about their children's asthma rates and IQ scores? Only about 25 percent of women who take acetaminophen during pregnancy do so because of a viral illness or fever. The majority take it for a painful condition, especially headaches (50%). A small proportion, 1.4 percent, take it apparently every night for the shocking indication of “sleep,” probably in combination with an over-the-counter antihistamine. (Those treating insomnia also had the highest cumulative acetaminophen exposures.) That's according to a survey by the University of California-San Diego of more than 2400 pregnant people in the United States and Canada, which, speaking of confounders, also found that acetaminophen users were more often obese, smokers, and on antidepressants. (Paediatr Perinat Epidemiol. 2020;34[3]:237; https://tinyurl.com/5bbvc797.) Birth Defects Risk One could imagine encouraging a pregnant person not to take acetaminophen for sleep. One could even imagine suggesting—uneasily, and making sure there's nothing between yourself and the closest exit—that the pregnant person might endure more minor aches and pains with fortitude. To quote that consensus statement on the possible dangers of prenatal acetaminophen, “[I]n the majority of women using APAP during pregnancy, its use might be without strong indications or have only limited efficacy for such conditions as chronic pain, back and knee pain, as well as headache.” (Nat Rev Endocrinol. 2021;17[12]:757; https://tinyurl.com/yc8buyad.) And fever? Fever and influenza during pregnancy are known independent risk factors for downstream neurodevelopmental disorders like spina bifida and anencephaly. That's why we encourage folic acid in pregnancy. Surely, we should aggressively treat fever in pregnancy? I reluctantly have to refer you to a Chinese study that matched 363 infants with neural tube defects (like spina bifida) against 523 matched controls. (Birth Defects Res A Clin Mol Teratol. 2007;79[4]:295.) This disturbing study reported a four- or fivefold risk of a neural tube defect for the children of mothers who had a maternal flu or fever or who took a prenatal “antipyretic,” usually acetaminophen (sometimes in this rural Chinese population, it was aspirin or phenacetin, an acetaminophen precursor withdrawn from the U.S. market in the 1970s over kidney injuries). And if a mother had a flu or fever and took “an antipyretic that was probably acetaminophen” to treat it? The odds risk for neural tube defects was 16-fold. That's right: Treating fever in this study quadrupled birth defect risks! But to wrap this up, definitely give that pregnant person with a fever and influenza some acetaminophen! We never figured out how it works, not since we isolated it from a coal tar waste product at the Bayer factory more than 100 years ago and started feeding it to people, and we can't really be bothered to study it properly either, but it will almost certainly be fine. DR. BIVENS works at emergency departments in Massachusetts, including St. Luke's in New Bedford and Beth Israel Deaconess Medical Center in Boston. He is double-boarded in emergency medicine and addiction medicine. Follow him on X @matt_bivens. Read his past columns at http://tinyurl.com/EMN-Bivens. Share this article on X and Facebook. Access the links in EMN by reading this on our website: www.EM-News.com. Comments? Write to us at [email protected].

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