Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Analgesic use — prevalence, biomonitoring and endocrine and reproductive effects

Key Points

  • Mild analgesics (hereafter, analgesics) consisting of paracetamol and NSAIDs are among the most used pharmaceutical drugs worldwide as well as the most released into the environment

  • Epidemiological data indicate a connection between maternal intake of analgesics and congenital reproductive abnormalities

  • Analgesics can have endocrine-disruptive actions in animals and humans of both sexes, from fetal life to adulthood

  • Medical and public awareness (especially that of pregnant women) must be increased about the potential hazards of analgesic use

Abstract

Paracetamol and NSAIDs, in particular acetylsalicylic acid (aspirin) and ibuprofen, are among the most used and environmentally released pharmaceutical drugs. The differences in international trends in the sale and consumption of mild analgesics reflect differences in marketing, governmental policies, habits, accessibility, disease patterns and the age distribution of each population. Biomonitoring indicates ubiquitous and high human exposure to paracetamol and to salicylic acid, which is the main metabolite of acetylsalicylic acid. Furthermore, evidence suggests that analgesics can have endocrine disruptive properties capable of altering animal and human reproductive function from fetal life to adulthood in both sexes. Medical and public awareness about these health concerns should be increased, particularly among pregnant women.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Temporal changes in the sales of acetylsalicylic acid, paracetamol and ibuprofen.
Figure 2: Temporal changes in the consumption of mild analgesics during pregnancy.
Figure 3: Consumption of mild analgesics across the three trimesters of pregnancy.
Figure 4: Simplified metabolism of analgesics.

Similar content being viewed by others

References

  1. Grosser, T., Smyth, E. & FitzGerald, G. A. in Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th edn (ed. Brunton, L. L.) 959–1004 (McGraw-Hill, 2011).

    Google Scholar 

  2. Roman, A. S. & Pernoll, M. L. in Current Diagnosis and Treatment, Obstetrics and Gynecology 14th edn (eds Alan, H. & Lauren, N.) 282–287 (McGraw-Hill, 2007).

    Google Scholar 

  3. Pongparadee, C. et al. Current considerations for the management of musculoskeletal pain in Asian countries: a special focus on cyclooxygenase-2 inhibitors and non-steroid anti-inflammation drugs. Int. J. Rheum. Dis. 15, 341–347 (2012).

    CAS  PubMed  Google Scholar 

  4. Hernandez, R. K., Werler, M. M., Romitti, P., Sun, L. & Anderka, M. Nonsteroidal antiinflammatory drug use among women and the risk of birth defects. Am. J. Obstet. Gynecol. 206, 228.e1–228.e8 (2012).

    CAS  Google Scholar 

  5. Jensen, M. S. et al. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology 21, 779–785 (2010). Reference 5 shows that prenatal exposure to paracetamol is associated with increased occurrence of congenital cryptorchidism.

    Article  PubMed  Google Scholar 

  6. Jensen, M. S. et al. Analgesics during pregnancy and cryptorchidism: additional analyses. Epidemiology 22, 610–612 (2011).

    PubMed  Google Scholar 

  7. Kristensen, D. M. et al. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum. Reprod. 26, 235–244 (2011). Reference 7 is a rare case of an integrated study combining epidemiology, in utero as well as ex vivo exposure in a laboratory experimental species (the rat). It suggests that intrauterine exposure to paracetamol, aspirin or ibuprofen is a risk factor for cryptorchidism and shows that paracetamol and aspirin can display antiandrogenic effects in the rat fetus.

    CAS  PubMed  Google Scholar 

  8. Lind, J. N. et al. Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997–2007. Pharmacoepidemiol. Drug Saf. 22, 783–793 (2013).

    PubMed  PubMed Central  Google Scholar 

  9. Philippat, C. et al. Analgesics during pregnancy and undescended testis. Epidemiology 22, 747–749 (2011).

    PubMed  Google Scholar 

  10. Snijder, C. A. et al. Intrauterine exposure to mild analgesics during pregnancy and the occurrence of cryptorchidism and hypospadia in the offspring: the Generation R Study. Hum. Reprod. 27, 1191–1201 (2012). Reference 10 shows that intrauterine exposure to paracetamol during the period of pregnancy when male differentiation takes place increases the risk of congenital cryptorchidism.

    PubMed  Google Scholar 

  11. Brune, K., Renner, B. & Tiegs, G. Acetaminophen/paracetamol: a history of errors, failures and false decisions. Eur. J. Pain 19, 953–965 (2015).

    CAS  PubMed  Google Scholar 

  12. Roberts, E. et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann. Rheum. Dis. 75, 552–559 (2016).

    CAS  PubMed  Google Scholar 

  13. Hudec, R., Božeková, L. & Tison̆ová, J. Consumption of three most widely used analgesics in six European countries. J. Clin. Pharm. Ther. 37, 78–80 (2012).

    CAS  PubMed  Google Scholar 

  14. Ahonen, R., Enlund, H., Klaukka, T. & Martikainen, J. Consumption of analgesics and anti-inflammatory drugs in the nordic countries between 1978–1988. Eur. J. Clin. Pharmacol. 41, 37–42 (1991).

    CAS  PubMed  Google Scholar 

  15. Hudec, R., Kriska, M., Bozekova, L. & Foltan, V. Comparison of NSAID consumption in Slovakia, Finland and Norway. Bratisl. Lek. Listy 109, 370–373 (2008).

    CAS  PubMed  Google Scholar 

  16. Kiivet, R. A., Bergman, U. & Sjöqvist, F. The use of drugs in Estonia compared to the Nordic countries. Eur. J. Clin. Pharmacol. 42, 511–515 (1992).

    CAS  PubMed  Google Scholar 

  17. McGettigan, P. & Henry, D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 10, e1001388 (2013).

    PubMed  PubMed Central  Google Scholar 

  18. McManus, P. et al. Pattern of non-steroidal anti-inflammatory drug use in Australia 1990–1994. A report from the Drug Utilization Sub-Committee of the Pharmaceutical Benefits Advisory Committee. Med. J. Aust. 164, 589–592 (1996).

    CAS  PubMed  Google Scholar 

  19. Mijatovic´, V. et al. Consumption of non-steroidal anti-inflammatory drugs in Serbia: a comparison with Croatia and Denmark during 2005–2008. Eur. J. Clin. Pharmacol. 67, 203–207 (2011).

    PubMed  Google Scholar 

  20. Agencia espanola de medicamentos y productos sanitarios. Utilización de medicamentos antiinflamatorios no esteroides (AINE) en España durante el periodo 2000–2012. [online] http://www.aemps.gob.es/medicamentosUsoHumano/observatorio/docs/AINE.pdf, (2014).

  21. Marklund, M. & Personne, M. Swedish Poisons Information Centre annual report 2014. Giftinformationscentralen [online] http://www.giftinformation.se/globalassets/publikationer/arsrapport-2014_engelska.pdf, (2014).

    Google Scholar 

  22. Black, R. A. & Hill, D. A. Over-the-counter medications in pregnancy. Am. Fam. Physician 67, 2517–2524 (2003).

    PubMed  Google Scholar 

  23. Thiele, K., Kessler, T., Arck, P., Erhardt, A. & Tiegs, G. Acetaminophen and pregnancy: short- and long-term consequences for mother and child. J. Reprod. Immunol. 97, 128–139 (2013). Reference 23 is a recent review that describes the short-term and long-term consequences for mother and child of intake of paracetamol during pregnancy. It stresses the urgent need to reconsider the safety and dosage of paracetamol during pregnancy and advocates the development of interdisciplinary research and clinical studies in this domain.

    CAS  PubMed  Google Scholar 

  24. Werler, M. M., Mitchell, A. A., Hernandez-Diaz, S. & Honein, M. A. Use of over-the-counter medications during pregnancy. Am. J. Obstet. Gynecol. 193, 771–777 (2005). Reference 24 reviews the patterns of over-the-counter pharmaceutical drug use among pregnant women and concludes that it is necessary to better inform pregnant women about risks and safety of these medications during pregnancy.

    PubMed  Google Scholar 

  25. Brandlistuen, R. E., Ystrom, E., Nulman, I., Koren, G. & Nordeng, H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int. J. Epidemiol. 42, 1702–1713 (2013).

    PubMed  PubMed Central  Google Scholar 

  26. Couto, A. C., Ferreira, J. D., Pombo-de-Oliveira, M. S. & Koifman, S. Pregnancy, maternal exposure to analgesic medicines, and leukemia in Brazilian children below 2 years of age. Eur. J. Cancer Prev. 24, 245–252 (2015).

    CAS  PubMed  Google Scholar 

  27. Eyers, S., Weatherall, M., Jefferies, S. & Beasley, R. Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. Clin. Exp. Allergy 41, 482–489 (2011).

    CAS  PubMed  Google Scholar 

  28. Goksör, E., Thengilsdottir, H., Alm, B., Norvenius, G. & Wennergren, G. Prenatal paracetamol exposure and risk of wheeze at preschool age. Acta Paediatr. 100, 1567–1571 (2011).

    PubMed  Google Scholar 

  29. Källén, B., Finnström, O., Nygren, K.-G. & Otterblad Olausson, P. Maternal drug use during pregnancy and asthma risk among children. Pediatr. Allergy Immunol. 24, 28–32 (2013).

    PubMed  Google Scholar 

  30. Li, M. et al. Maternal influenza-like illness, medication use during pregnancy and risk of congenital heart defects in offspring. J. Matern. Fetal Neonatal Med. 27, 807–811 (2014).

    CAS  PubMed  Google Scholar 

  31. Liew, Z., Ritz, B., Rebordosa, C., Lee, P.-C. & Olsen, J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 168, 313–320 (2014).

    PubMed  Google Scholar 

  32. Marsh, C. A., Cragan, J. D., Alverson, C. J. & Correa, A. Case–control analysis of maternal prenatal analgesic use and cardiovascular malformations: Baltimore–Washington Infant Study. Am. J. Obstet. Gynecol. 211, 404.e1–404.e9 (2014).

    Google Scholar 

  33. Shaheen, S. O., Newson, R. B., Smith, G. D. & Henderson, A. J. Prenatal paracetamol exposure and asthma: further evidence against confounding. Int. J. Epidemiol. 39, 790–794 (2010).

    PubMed  Google Scholar 

  34. Sordillo, J. E. et al. Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children. J. Allergy Clin. Immunol. 135, 441–448 (2015).

    CAS  PubMed  Google Scholar 

  35. Amundsen, S., Nordeng, H., Nezvalová-Henriksen, K., Stovner, L. J. & Spigset, O. Pharmacological treatment of migraine during pregnancy and breastfeeding. Nat. Rev. Neurol. 11, 209–219 (2015).

    PubMed  Google Scholar 

  36. Alano, M. A., Ngougmna, E., Ostrea, E. M. & Konduri, G. G. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 107, 519–523 (2001).

    CAS  PubMed  Google Scholar 

  37. Siu, S. S., Yeung, J. H. & Lau, T. K. A study on placental transfer of diclofenac in first trimester of human pregnancy. Hum. Reprod. 15, 2423–2425 (2000).

    CAS  PubMed  Google Scholar 

  38. Briggs, G. G. & Freeman, R. K. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk (Lippincott Williams & Wilkins, 2015).

    Google Scholar 

  39. Malm, H. & Borisch, C. in Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment (eds Schaeffer, C. et al.) 27–58 (Elsevier, 2015).

    Google Scholar 

  40. Hassoun-Barhamji, R., Raia Barjat, T. & Chauleur, C. In the era of self-medication, what do pregnant women know about anti-inflammatory drugs? Therapie 70, 369–376 (in French) (2015).

    PubMed  Google Scholar 

  41. Kassaw, C. & Wabe, N. T. Pregnant women and non-steroidal anti-inflammatory drugs: knowledge, perception and drug consumption pattern during pregnancy in ethiopia. N. Am. J. Med. Sci. 4, 72–76 (2012).

    PubMed  PubMed Central  Google Scholar 

  42. Mashayekhi, S. O., Dilmaghanizadeh, M., Fardiazar, Z., Bamdad-Moghadam, R. & Ghandforoush-Sattari, F. Study of awareness among pregnant women of the effects of drugs on the fetus and mother in Iran. Health Policy 91, 89–93 (2009).

    PubMed  Google Scholar 

  43. Collins, E. Maternal and fetal effects of acetaminophen and salicylates in pregnancy. Obstet. Gynecol. 58, 57S–62S (1981).

    CAS  PubMed  Google Scholar 

  44. Niederhoff, H. & Zahradnik, H. P. Analgesics during pregnancy. Am. J. Med. 75, 117–120 (1983).

    CAS  PubMed  Google Scholar 

  45. Rumack, C. M. et al. Neonatal intracranial hemorrhage and maternal use of aspirin. Obstet. Gynecol. 58, 52S–56S (1981).

    CAS  PubMed  Google Scholar 

  46. Stuart, M. J., Gross, S. J., Elrad, H. & Graeber, J. E. Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis. N. Engl. J. Med. 307, 909–912 (1982).

    CAS  PubMed  Google Scholar 

  47. Wallenburg, H. C., Dekker, G. A., Makovitz, J. W. & Rotmans, P. Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotensin-sensitive primigravidae. Lancet 1, 1–3 (1986).

    CAS  PubMed  Google Scholar 

  48. Radin, R. G. et al. Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss. J. Clin. Invest. 125, 3619–3626 (2015).

    PubMed  PubMed Central  Google Scholar 

  49. Van Marter, L. J., Hernandez-Diaz, S., Werler, M. M., Louik, C. & Mitchell, A. A. Nonsteroidal antiinflammatory drugs in late pregnancy and persistent pulmonary hypertension of the newborn. Pediatrics 131, 79–87 (2013).

    PubMed  PubMed Central  Google Scholar 

  50. Nezvalová-Henriksen, K., Spigset, O. & Nordeng, H. Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospective cohort study. BJOG 120, 948–959 (2013).

    PubMed  PubMed Central  Google Scholar 

  51. Cahill, J. D., Furlong, E. T., Burkhardt, M. R., Kolpin, D. & Anderson, L. G. Determination of pharmaceutical compounds in surface- and ground-water samples by solid-phase extraction and high-performance liquid chromatography-electrospray ionization mass spectrometry. J. Chromatogr. A 1041, 171–180 (2004).

    CAS  PubMed  Google Scholar 

  52. Bouissou-Schurtz, C. et al. Ecological risk assessment of the presence of pharmaceutical residues in a French national water survey. Regul. Toxicol. Pharmacol. 69, 296–303 (2014). Reference 52 assessed the ecological risk inherent in the release in water of pharmaceutical residues, including those of several analgesics.

    CAS  PubMed  Google Scholar 

  53. Bedner, M. & MacCrehan, W. A. Transformation of acetaminophen by chlorination produces the toxicants 1,4-benzoquinone and N-acetyl-p-benzoquinone imine. Environ. Sci. Technol. 40, 516–522 (2006).

    CAS  PubMed  Google Scholar 

  54. Ashton, D., Hilton, M. & Thomas, K. V. Investigating the environmental transport of human pharmaceuticals to streams in the United Kingdom. Sci. Total Environ. 333, 167–184 (2004).

    CAS  PubMed  Google Scholar 

  55. Ternes, T. A. Occurrence of drugs in German sewage treatment plants and rivers. Water Res. 32, 3245–3260 (1998).

    CAS  Google Scholar 

  56. Naidoo, V. & Swan, G. E. Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 149, 269–274 (2009).

    CAS  PubMed  Google Scholar 

  57. Oaks, J. L. et al. Diclofenac residues as the cause of vulture population decline in Pakistan. Nature 427, 630–633 (2004).

    CAS  PubMed  Google Scholar 

  58. Zorrilla, I., Martinez, R., Taggart, M. A. & Richards, N. Suspected flunixin poisoning of a wild Eurasian Griffon Vulture from Spain. Conserv. Biol. 29, 587–592 (2015).

    PubMed  Google Scholar 

  59. Camann, D. E. et al. Acetaminophen, pesticide, and diethylhexyl phthalate metabolites, anandamide, and fatty acids in deciduous molars: potential biomarkers of perinatal exposure. J. Expo. Sci. Environ. Epidemiol. 23, 190–196 (2013).

    CAS  PubMed  Google Scholar 

  60. Berlin, C. M., Yaffe, S. J. & Ragni, M. Disposition of acetaminophen in milk, saliva, and plasma of lactating women. Pediatr. Pharmacol. (New York) 1, 135–141 (1980).

    CAS  Google Scholar 

  61. Ellfolk, M. & Hultzsch, S. in Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment (eds Schaeffer, C. et al.) 653–670 (Elsevier, 2015).

    Google Scholar 

  62. Naga Rani, M. A., Joseph, T. & Narayanan, R. Placental transfer of paracetamol. J. Indian Med. Assoc. 87, 182–183 (1989).

    CAS  PubMed  Google Scholar 

  63. Hutchinson, S. et al. Use of common migraine treatments in breast-feeding women: a summary of recommendations. Headache 53, 614–627 (2013).

    PubMed  PubMed Central  Google Scholar 

  64. Jacqz-Aigrain, E. et al. Excretion of ketoprofen and nalbuphine in human milk during treatment of maternal pain after delivery. Ther. Drug Monit. 29, 815–818 (2007).

    CAS  PubMed  Google Scholar 

  65. Townsend, R. J. et al. Excretion of ibuprofen into breast milk. Am. J. Obstet. Gynecol. 149, 184–186 (1984).

    CAS  PubMed  Google Scholar 

  66. Walter, K. & Dilger, C. Ibuprofen in human milk. Br. J. Clin. Pharmacol. 44, 211–212 (1997).

    CAS  PubMed  Google Scholar 

  67. Paterson, J. R. et al. Salicylic acid sans aspirin in animals and man: persistence in fasting and biosynthesis from benzoic acid. J. Agric. Food Chem. 56, 11648–11652 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Blacklock, C. J. et al. Salicylic acid in the serum of subjects not taking aspirin. Comparison of salicylic acid concentrations in the serum of vegetarians, non-vegetarians, and patients taking low dose aspirin. J. Clin. Pathol. 54, 553–555 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Lapczynski, A. et al. Fragrance material review on methyl salicylate. Food Chem. Toxicol. 45, S428–S452 (2007).

    PubMed  Google Scholar 

  70. Buttery, R. G., Kamm, J. A. & Ling, L. C. Volatile components of red clover leaves, flowers, and seed pods: possible insect attractants. J. Agric. Food Chem. 32, 254–256 (1984).

    CAS  Google Scholar 

  71. Modick, H., Weiss, T., Dierkes, G., Brüning, T. & Koch, H. M. Ubiquitous presence of paracetamol in human urine: sources and implications. Reproduction 147, R105–R117 (2014).

    CAS  PubMed  Google Scholar 

  72. Kao, J., Faulkner, J. & Bridges, J. W. Metabolism of aniline in rats, pigs and sheep. Drug Metab. Dispos. 6, 549–555 (1978).

    CAS  PubMed  Google Scholar 

  73. Modick, H. et al. Rapid determination of N-acetyl-4-aminophenol (paracetamol) in urine by tandem mass spectrometry coupled with on-line clean-up by two dimensional turbulent flow/reversed phase liquid chromatography. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 925, 33–39 (2013). Reference 73 establishes that paracetamol is ubiquitous in the urine of the German population, including individuals with no obvious paracetamol exposure such as intake of medications containing paracetamol, or occupational exposure to aniline. Aniline is a precursor of paracetamol used in the production of many industrial compounds and also present in food, cosmetics and cigarette smoke.

    CAS  PubMed  Google Scholar 

  74. Palmiotto, G., Pieraccini, G., Moneti, G. & Dolara, P. Determination of the levels of aromatic amines in indoor and outdoor air in Italy. Chemosphere 43, 355–361 (2001).

    CAS  PubMed  Google Scholar 

  75. Iwersen-Bergmann, S. & Schmoldt, A. Acute intoxication with aniline: detection of acetaminophen as aniline metabolite. Int. J. Legal Med. 113, 171–174 (2000).

    CAS  PubMed  Google Scholar 

  76. Lewalter, J. & Korallus, U. Blood protein conjugates and acetylation of aromatic amines. New findings on biological monitoring. Int. Arch. Occup. Environ. Health 56, 179–196 (1985).

    CAS  PubMed  Google Scholar 

  77. Holm, J. B. et al. Aniline is rapidly converted into paracetamol impairing male reproductive development. Toxicol. Sci. 148, 288–298 (2015). Reference 77 directly shows the rapid liver conversion of aniline into paracetamol in the mouse and that aniline, like paracetamol, exerts antiandrogenic effects.

    CAS  PubMed  Google Scholar 

  78. Nielsen, J. K. S. et al. N-acetyl-4-aminophenol (paracetamol) in urine samples of 6–11-year-old Danish school children and their mothers. Int. J. Hyg. Environ. Health 218, 28–33 (2015).

    CAS  PubMed  Google Scholar 

  79. Dierkes, G. et al. N-acetyl-4-aminophenol (paracetamol), N-acetyl-2-aminophenol and acetanilide in urine samples from the general population, individuals exposed to aniline and paracetamol users. Int. J. Hyg. Environ. Health 217, 592–599 (2014).

    CAS  PubMed  Google Scholar 

  80. Scientific Committee on Consumer Safety. Opinion on p-aminophenol. European Commission [online] http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_078.pdf, (2011).

  81. Love, D. C., Halden, R. U., Davis, M. F. & Nachman, K. E. Feather meal: a previously unrecognized route for reentry into the food supply of multiple pharmaceuticals and personal care products (PPCPs). Environ. Sci. Technol. 46, 3795–3802 (2012).

    CAS  PubMed  Google Scholar 

  82. Boisen, K. A. et al. Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet 363, 1264–1269 (2004).

    CAS  PubMed  Google Scholar 

  83. Serrano, T., Chevrier, C., Multigner, L., Cordier, S. & Jegou, B. International geographic correlation study of the prevalence of disorders of male reproductive health. Hum. Reprod. 28, 1974–1986 (2013).

    CAS  PubMed  Google Scholar 

  84. Berkowitz, G. S. & Lapinski, R. H. Risk factors for cryptorchidism: a nested case–control study. Paediatr. Perinat. Epidemiol. 10, 39–51 (1996). Reference 84 is the first study to establish that use of analgesics during pregnancy is a risk factor for cryptorchidism.

    CAS  PubMed  Google Scholar 

  85. Skakkebaek, N. E. et al. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol. Rev. 96, 55–97 (2016).

    CAS  PubMed  Google Scholar 

  86. Correy, J. F. et al. Use of prescription drugs in the first trimester and congenital malformations. Aust. N. Z. J. Obstet. Gynaecol. 31, 340–344 (1991).

    CAS  PubMed  Google Scholar 

  87. Slone, D. et al. Aspirin and congenital malformations. Lancet 1, 1373–1375 (1976).

    CAS  PubMed  Google Scholar 

  88. Keim, S. A. & Klebanoff, M. A. Aspirin use and miscarriage risk. Epidemiology 17, 435–439 (2006).

    PubMed  Google Scholar 

  89. Li, D.-K., Liu, L. & Odouli, R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ 327, 368 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Nakhai-Pour, H. R., Broy, P., Sheehy, O. & Bérard, A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ 183, 1713–1720 (2011).

    PubMed  PubMed Central  Google Scholar 

  91. Nielsen, G. L., Skriver, M. V., Pedersen, L. & Sørensen, H. T. Danish group reanalyses miscarriage in NSAID users. BMJ 328, 109 (2004).

    PubMed  PubMed Central  Google Scholar 

  92. Daniel, S. et al. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ 186, E177–E182 (2014).

    PubMed  PubMed Central  Google Scholar 

  93. van Lingen, R. A. et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch. Dis. Child. Fetal Neonatal Ed. 80, F59–F63 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Welsh, M. et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J. Clin. Invest. 118, 1479–1490 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Axelstad, M. et al. Mixtures of endocrine-disrupting contaminants induce adverse developmental effects in preweaning rats. Reproduction 147, 489–501 (2014).

    CAS  PubMed  Google Scholar 

  96. Dean, A., Mungall, W., McKinnell, C. & Sharpe, R. M. Prostaglandins, masculinization and its disorders: effects of fetal exposure of the rat to the cyclooxygenase inhibitor — indomethacin. PLoS ONE 8, e62556 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. van den Driesche, S. et al. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model. Sci. Transl Med. 7, 288ra80 (2015). Reference 97 shows, using a xenograft model consisting of castrated host mice bearing human fetal testis xenografts, that paracetamol can exert antiandrogenic effects.

    PubMed  PubMed Central  Google Scholar 

  98. Kristensen, D. M. et al. Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti-androgenic in the rat foetal testis. Int. J. Androl. 35, 377–384 (2012).

    CAS  PubMed  Google Scholar 

  99. Holm, J. B. et al. Intrauterine exposure to paracetamol and aniline impairs female reproductive development by reducing follicle reserves and fertility. Toxicol. Sci. 150, 178–189 (2016). Reference 99 provides evidence that aniline and paracetamol administered in utero to mice block primordial germ cell proliferation, subsequetly leading to reduced follicle reserves and ultimately compromizing fertility in the adult.

    CAS  PubMed  Google Scholar 

  100. Dean, A. et al. Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences. Sci. Rep. 6, 19789 (2016). Reference 100 raises concern about the use of the analgesics indomethacin or paracetamol during pregnancy by showing that exposure to these medications in pregnant rats affects germ cell development and reproductive function in resulting offspring (F1) or in the F2 generation.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Gupta, C. Prostaglandins masculinize the mouse genital tract. Endocrinology 124, 1781–1787 (1989).

    CAS  PubMed  Google Scholar 

  102. Gupta, C. & Goldman, A. S. The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitalia in mice. Proc. Natl Acad. Sci. USA 83, 4346–4349 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Philibert, P. et al. Unilateral cryptorchidism in mice mutant for Ptgds. Hum. Mutat. 34, 278–282 (2013).

    CAS  PubMed  Google Scholar 

  104. Jégou, B. Paracetamol-induced endocrine disruption in human fetal testes. Nat. Rev. Endocrinol. 11, 453–454 (2015).

    PubMed  Google Scholar 

  105. Mazaud-Guittot, S. et al. Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent. J. Clin. Endocrinol. Metab. 98, E1757–E1767 (2013). Reference 105 was the first study to demonstrate that in the human fetal testis, paracetamol, aspirin and indomethacin can induce direct ex vivo and important endocrine disruptive effects. This particularly noticeable action is due to a paracetamol-induced inhibition of the production of insulin-like 3, which is responsible for the first phase of testicular descent, as well as of prostaglandin E 2.

    CAS  PubMed  Google Scholar 

  106. Foresta, C., Zuccarello, D., Garolla, A. & Ferlin, A. Role of hormones, genes, and environment in human cryptorchidism. Endocr. Rev. 29, 560–580 (2008).

    CAS  PubMed  Google Scholar 

  107. Ivell, R. & Anand-Ivell, R. Biology of insulin-like factor 3 in human reproduction. Hum. Reprod. Update 15, 463–476 (2009).

    CAS  PubMed  Google Scholar 

  108. Scott, J. E. & Persaud, T. V. A quantitative study of the effects of acetylsalicylic acid on spermatogenesis and organs of the rat. Int. J. Fertil. 23, 282–287 (1978).

    CAS  PubMed  Google Scholar 

  109. Biswas, N. M., Sanyal, S. & Patra, P. B. Antispermatogenic effect of aspirin and its prevention by prostaglandin E2 . Andrologia 10, 137–141 (1978).

    CAS  PubMed  Google Scholar 

  110. Didolkar, A. K., Patel, P. B. & Roychowdhury, D. Effect of aspirin on spermatogenesis in mature and immature rats. Int. J. Androl. 3, 585–593 (1980). Reference 110 is one of the earliest studies showing that aspirin impairs testicular function in both immature and adult rats.

    CAS  PubMed  Google Scholar 

  111. Yano, C. L. & Dolder, H. Rat testicular structure and ultrastructure after paracetamol treatment. Contraception 66, 463–467 (2002).

    CAS  PubMed  Google Scholar 

  112. Didolkar, A. K., Gurjar, A., Joshi, U. M., Sheth, A. R. & Roychowdhury, D. Effects of aspirin on blood plasma levels of testosterone, LH and FSH in maturing male rats. Int. J. Androl. 3, 312–318 (1980).

    CAS  PubMed  Google Scholar 

  113. Pawlikowski, M., Kula, K. & Lyson´, K. Indomethacin suppresses basal but not HCG-stimulated testosterone secretion in the rat. Endokrynol. Pol. 37, 139–142 (1986).

    CAS  PubMed  Google Scholar 

  114. Saksena, S. K., Lau, I. F., Bartke, A. & Chang, M. C. Effect of indomethacin on blood plasma levels of LH and testosterone in male rats. J. Reprod. Fertil. 42, 311–317 (1975).

    CAS  PubMed  Google Scholar 

  115. Sanyal, S., Deb, C., Patra, P. B. & Biswas, N. M. In vitro studies on histochemical localization of testicular δ5-3β-hydroxysteroid dehydrogenase activity from indomethacin pretreated rats — effect of prostaglandins and luteinizing hormone. Andrologia 11, 157–162 (1979).

    CAS  PubMed  Google Scholar 

  116. Stutz, G. et al. Functional activity of mouse sperm was not affected by low doses of aspirin-like drugs. Arch. Androl. 44, 117–128 (2000).

    CAS  PubMed  Google Scholar 

  117. Martini, A. C. et al. Chronic administration of nonsteroidal-antiinflammatory drugs (NSAIDS): effects upon mouse reproductive functions. Rev. Fac. Cien. Med. Univ. Nac. Cordoba 65, 47–59 (2008).

    Google Scholar 

  118. Ji, K. et al. Effects of non-steroidal anti-inflammatory drugs on hormones and genes of the hypothalamic–pituitary–gonad axis, and reproduction of zebrafish. J. Hazard. Mater. 254–255, 242–251 (2013).

    PubMed  Google Scholar 

  119. Morthorst, J. E., Lister, A., Bjerregaard, P. & Van Der Kraak, G. Ibuprofen reduces zebrafish PGE2 levels but steroid hormone levels and reproductive parameters are not affected. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 157, 251–257 (2013).

    CAS  PubMed  Google Scholar 

  120. Gates, M. A., Araujo, A. B., Hall, S. A., Wittert, G. A. & McKinlay, J. B. Non steroidal anti-inflammatory drug use and levels of oestrogens and androgens in men. Clin. Endocrinol. (Oxf.) 76, 272–280 (2012).

    CAS  Google Scholar 

  121. Di Luigi, L. et al. Do non-steroidal anti-inflammatory drugs influence the steroid hormone milieu in male athletes? Int. J. Sports Med. 28, 809–814 (2007).

    CAS  PubMed  Google Scholar 

  122. Barkay, J., Harpaz-Kerpel, S., Ben-Ezra, S., Gordon, S. & Zuckerman, H. The prostaglandin inhibitor effect of antiinflammatory drugs in the therapy of male infertility. Fertil. Steril. 42, 406–411 (1984).

    CAS  PubMed  Google Scholar 

  123. Conte, D. et al. Aspirin inhibition of naloxone-induced luteinizing hormone secretion in man. J. Clin. Endocrinol. Metab. 81, 1772–1775 (1996).

    CAS  PubMed  Google Scholar 

  124. Di Luigi, L., Guidetti, L., Romanelli, F., Baldari, C. & Conte, D. Acetylsalicylic acid inhibits the pituitary response to exercise-related stress in humans. Med. Sci. Sports Exerc. 33, 2029–2035 (2001).

    CAS  PubMed  Google Scholar 

  125. Conte, D. et al. Aspirin inhibits androgen response to chorionic gonadotropin in humans. Am. J. Physiol. 277, E1032–E1037 (1999). Reference 125 clearly establishes that aspirin treatment inhibits the androgen response to human chorionic gonadropin in human male volunteers.

    CAS  PubMed  Google Scholar 

  126. Pruthi, R. S., Derksen, J. E. & Moore, D. A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy. BJU Int. 93, 275–278 (2004).

    CAS  PubMed  Google Scholar 

  127. Ball, K. D., Levell, M. J. & Pickup, M. E. The effect of ibuprofen on the excretion of steroid metabolites. Clin. Chim. Acta 124, 23–29 (1982).

    CAS  PubMed  Google Scholar 

  128. Albert, O. et al. Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Hum. Reprod. 28, 1890–1898 (2013).

    CAS  PubMed  Google Scholar 

  129. De Kretser, D. & Kerr, J. in The Physiology of Reproduction (eds Knobil, E. et al.) 837–932 (Raven Press, 1988).

    Google Scholar 

  130. Prince, F. P. The triphasic nature of Leydig cell development in humans, and comments on nomenclature. J. Endocrinol. 168, 213–216 (2001).

    CAS  PubMed  Google Scholar 

  131. Sten, T., Finel, M., Ask, B., Rane, A. & Ekström, L. Non-steroidal anti-inflammatory drugs interact with testosterone glucuronidation. Steroids 74, 971–977 (2009).

    CAS  PubMed  Google Scholar 

  132. Tilakaratne, A. & Soory, M. The modulation of androgen metabolism by estradiol, minocycline, and indomethacin in a cell culture model. J. Periodontol. 73, 585–590 (2002).

    CAS  PubMed  Google Scholar 

  133. Karim, S. M. & Hillier, K. Prostaglandins in the control of animal and human reproduction. Br. Med. Bull. 35, 173–180 (1979). Reference 133 is an early review on the physiological involvement of prostaglandins in animal and human reproduction.

    CAS  PubMed  Google Scholar 

  134. Sirois, J. et al. Cyclooxygenase-2 and its role in ovulation: a 2004 account. Hum. Reprod. Update 10, 373–385 (2004).

    CAS  PubMed  Google Scholar 

  135. Duggan, C., Wang, C.-Y., Xiao, L. & McTiernan, A. Aspirin and serum estrogens in postmenopausal women: a randomized controlled clinical trial. Cancer Prev. Res. (Phila.) 7, 906–912 (2014).

    CAS  Google Scholar 

  136. Fortner, R. T. et al. Analgesic use and patterns of estrogen metabolism in premenopausal women. Horm. Cancer 5, 104–112 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Bauer, S. R. et al. Analgesic use in relation to sex hormone and prolactin concentrations in premenopausal women. Cancer Causes Control 24, 1087–1097 (2013).

    PubMed  PubMed Central  Google Scholar 

  138. Cramer, D. W. et al. Basal hormone levels in women who use acetaminophen for menstrual pain. Fertil. Steril. 70, 371–373 (1998).

    CAS  PubMed  Google Scholar 

  139. Gates, M. A., Tworoger, S. S., Eliassen, A. H., Missmer, S. A. & Hankinson, S. E. Analgesic use and sex steroid hormone concentrations in postmenopausal women. Cancer Epidemiol. Biomarkers Prev. 19, 1033–1041 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. McTiernan, A. et al. Relation of demographic factors, menstrual history, reproduction and medication use to sex hormone levels in postmenopausal women. Breast Cancer Res. Treat. 108, 217–231 (2008).

    PubMed  Google Scholar 

  141. Rogers, S. M., Back, D. J., Stevenson, P. J., Grimmer, S. F. & Orme, M. L. Paracetamol interaction with oral contraceptive steroids: increased plasma concentrations of ethinyloestradiol. Br. J. Clin. Pharmacol. 23, 721–725 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Meyboom, R. H. B., Heymeijer, G. W. J., van den Bemt, P. M. L. A. & de Koning, G. H. P. Disturbance of menstruation as a side-effect of nonsteroidal anti-inflammatory drugs (NSAIDs). Pharmacoepidemiol. Drug Saf. 4, 161–163 (1995). Reference 142 stresses the possibility that NSAIDs interrupt, delay or decrease menstrual periods in women.

    Google Scholar 

  143. Bata, M. S., Al-Ramahi, M., Salhab, A. S., Gharaibeh, M. N. & Schwartz, J. Delay of ovulation by meloxicam in healthy cycling volunteers: a placebo-controlled, double-blind, crossover study. J. Clin. Pharmacol. 46, 925–932 (2006).

    CAS  PubMed  Google Scholar 

  144. Salman, S., Sherif, B. & Al-Zohyri, A. Effects of some non steroidal anti-inflammatory drugs on ovulation in women with mild musculoskeletal pain. Ann. Rheum. Dis. 74, 117–118 (2015).

    Google Scholar 

  145. Hester, K. E., Harper, M. J. K. & Duffy, D. M. Oral administration of the cyclooxygenase-2 (COX-2) inhibitor meloxicam blocks ovulation in non-human primates when administered to simulate emergency contraception. Hum. Reprod. 25, 360–367 (2010).

    CAS  PubMed  Google Scholar 

  146. Acerini, C. L., Miles, H. L., Dunger, D. B., Ong, K. K. & Hughes, I. A. The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Arch. Dis. Child. 94, 868–872 (2009).

    CAS  PubMed  Google Scholar 

  147. Wohlfahrt-Veje, C. et al. Acquired cryptorchidism is frequent in infancy and childhood. Int. J. Androl. 32, 423–428 (2009).

    PubMed  Google Scholar 

  148. Scorer, C. G. The descent of the testis. Arch. Dis. Child. 39, 605–609 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Swan, S. H. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ. Res. 108, 177–184 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Swan, S. H. et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ. Health Perspect. 113, 1056–1061 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Dean, A. & Sharpe, R. M. Clinical review: anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J. Clin. Endocrinol. Metab. 98, 2230–2238 (2013).

    CAS  PubMed  Google Scholar 

  152. Hsieh, M. H., Breyer, B. N., Eisenberg, M. L. & Baskin, L. S. Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption. Curr. Urol. Rep. 9, 137–142 (2008).

    PubMed  Google Scholar 

  153. Hsieh, M. H. et al. Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. Hum. Reprod. 27, 1577–1580 (2012).

    PubMed  PubMed Central  Google Scholar 

  154. Albert, O. & Jégou, B. A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood. Hum. Reprod. Update 20, 231–249 (2014).

    CAS  PubMed  Google Scholar 

  155. World Health Organization. WHO collaborating centre for drug statistics methodology, guidelines for ATC classification and DDD assignment 2013. [online] http://www.whocc.no/filearchive/publications/1_2013guidelines.pdf, (2012).

  156. Glover, D. D., Amonkar, M., Rybeck, B. F. & Tracy, T. S. Prescription, over-the-counter, and herbal medicine use in a rural, obstetric population. Am. J. Obstet. Gynecol. 188, 1039–1045 (2003).

    PubMed  Google Scholar 

  157. Henry, A. & Crowther, C. Patterns of medication use during and prior to pregnancy: the MAP study. Aust. N. Z. J. Obstet. Gynaecol. 40, 165–172 (2000).

    CAS  PubMed  Google Scholar 

  158. Pastore, L. M., Hertz-Picciotto, I. & Beaumont, J. J. Risk of stillbirth from medications, illnesses and medical procedures. Paediatr. Perinat. Epidemiol. 13, 421–430 (1999).

    CAS  PubMed  Google Scholar 

  159. Rebordosa, C. et al. Acetaminophen use during pregnancy: effects on risk for congenital abnormalities. Am. J. Obstet. Gynecol. 198, 178.e1–178.e7 (2008).

    Google Scholar 

  160. Saxén, I. Associations between oral clefts and drugs taken during pregnancy. Int. J. Epidemiol. 4, 37–44 (1975).

    PubMed  Google Scholar 

  161. Stephansson, O. et al. Drug use during pregnancy in Sweden — assessed by the Prescribed Drug Register and the Medical Birth Register. Clin. Epidemiol. 3, 43–50 (2011).

    PubMed  PubMed Central  Google Scholar 

  162. Wen, S. W. et al. Patterns of pregnancy exposure to prescription FDA C, D and X drugs in a Canadian population. J. Perinatol. 28, 324–329 (2008).

    CAS  PubMed  Google Scholar 

  163. Gupta, U., Cook, J. C., Tassinari, M. S. & Hurtt, M. E. Comparison of developmental toxicology of aspirin (acetylsalicylic acid) in rats using selected dosing paradigms. Birth Defects Res. B. Dev. Reprod. Toxicol. 68, 27–37 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' research is funded by The Danish Council for Independent Research (Medical Sciences) [D.M.K.], the Fondation pour la Recherche Médicale [P.G.], Inserm (Institut national de la santé et de la recherche médicale) [B.J., S.M.-G.], Rennes 1 University [L.L.], EHESP–School of Public Health [B.J., T.S.] and ANSM (Agence Nationale de la Sécurité du Médicament; grants N° AAP-2012-037 and N° HAP-2014-073) [B.J.]. We also thank T. Renberg from the Swedish Health Agency and T. Partio from the Finnish social security institution KELA for providing us with pharmaceutical sales data.

Author information

Authors and Affiliations

Authors

Contributions

D.M.K., S.M.-G., P.G., L.L., T.S., and B.J. researched data for the article. D.M.K., S.M.-G., K.M.M. and B.J. made substantial contributions to discussions of the content. D.M.K., S.M.-G. and B.J. wrote the article. D.M.K., S.M.-G., L.L., K.M.M. and B.J. reviewed and/or edited the article before submission.

Corresponding authors

Correspondence to David M. Kristensen or Bernard Jégou.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Supplementary information

Supplementary S1 (table)

The history of consumption of analgesics by pregnant women. (PDF 305 kb)

Supplementary S2 (figure)

Worldwide consumption of mild analgesics during pregnancy. (PDF 221 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kristensen, D., Mazaud-Guittot, S., Gaudriault, P. et al. Analgesic use — prevalence, biomonitoring and endocrine and reproductive effects. Nat Rev Endocrinol 12, 381–393 (2016). https://doi.org/10.1038/nrendo.2016.55

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2016.55

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing