Drug Safety

, Volume 33, Issue 8, pp 631–642

Safety of Oseltamivir in Pregnancy

A Review of Preclinical and Clinical Data
  • Barbara Donner
  • Viswanathan Niranjan
  • Gerhard Hoffmann
Review Article

Abstract

Pregnant women with influenza are at increased risk of morbidity, particularly due to respiratory complications. A high excess mortality rate among pregnant women has been observed in previous influenza pandemics and healthcare agencies have provided recommendations on the use of oseltamivir to treat pregnant women who are infected with the pandemic (H1N1) 2009 virus. This article reviews pre-clinical and clinical data to assess the safety of oseltamivir administered during pregnancy, in the context of the effects of influenza on adverse pregnancy outcomes and fetal malformations.

The effects of influenza during pregnancy, whether mediated directly by the virus or by fever or other events secondary to the underlying infection, are not yet well understood, but some data indicate an increased risk of birth defects in women infected with influenza during the first trimester. Animal and toxicology studies do not suggest that clinically effective dosages of oseltamivir have the potential to produce adverse effects on fetal development. Additionally, transplacental transfer of the drug and its active metabolite was very limited and not detectable at normal therapeutic doses in an ex vivo human placenta model.

To investigate the safety of oseltamivir in pregnancy, the Roche oseltamivir safety database was searched for all exposures to oseltamivir during pregnancy in the 9 years up to 14 December 2008. In addition, a search of the literature was carried out. Of 232 maternal exposures to oseltamivir in the Roche database, pregnancy outcomes were known for 115 of these exposures. The incidence of adverse pregnancy outcomes was as follows: spontaneous abortions 6.1% (7/115), therapeutic abortions 11.3% (13/115) and pre-term deliveries 2.1% (2/94 live births), values that are not higher than background incidence rates. Fetal outcomes were known in 100 of the 232 exposures. For the nine cases of birth defect that were reported, the timing of oseltamivir exposure in relation to the sensitive period for inducing the birth defect was analysed. Two cases of ventricular septal defect, a more common birth defect, and one case of anophthalmos, an uncommon birth defect, were consistent with exposure to oseltamivir during the sensitive period for these birth defects. For other birth defects, there was either no exposure to oseltamivir during the sensitive period for the defect or insufficient information for assessment. These findings were consistent with other reports in the published literature, including a series of 79 Japanese women exposed to oseltamivir during the first trimester.

Together with the other evidence reviewed herein, review of the company safety database suggests that oseltamivir is unlikely to cause adverse pregnancy or fetal outcomes, but available data are limited. Clinicians who use oseltamivir in pregnant women should consider the available safety information, the pathogenicity of the circulating influenza virus strain, the woman’s general health and the guidance provided by health authorities. Roche will continue to monitor all reports of oseltamivir use during pregnancy.

References

  1. 1.
    Nicholson KG. Human influenza. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of influenza. Oxford: Blackwell Science, 1998: 219–64Google Scholar
  2. 2.
    Ruf BR, Szucs T. Reducing the burden of influenza-associated complications with antiviral therapy. Infection 2009; 37(3): 186–96PubMedCrossRefGoogle Scholar
  3. 3.
    Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep 2008; 57(RR-7): 1–60PubMedGoogle Scholar
  4. 4.
    Harris JW. Influenza occurring in pregnant women. JAMA 1919; 72: 978–80CrossRefGoogle Scholar
  5. 5.
    Nuzum JW, Pilot I, Stangl FH, et al. Pandemic influenza and pneumonia in a large civilian hospital. JAMA 1918; 71: 1562–5CrossRefGoogle Scholar
  6. 6.
    He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999; 37(6): 471–84PubMedCrossRefGoogle Scholar
  7. 7.
    Tamiflu SmPC. Tamiflu summary of product characteristics [online]. Available from URL: http://www.medicines.org.uk/emc/document.aspx?documentid=10446[Accessed 2010 Jun 1]
  8. 8.
    Gilsdorf A, Poggensee G. Influenza A(H1N1)v in Germany: the first 10,000 cases. Euro Surveill 2009; 14(34): pii: 19318Google Scholar
  9. 9.
    Centers for Disease Control and Prevention (CDC). 2009 pandemic influenza A (H1N1) virus infections: Chicago, Illinois, April-July 2009. MMWR Morb Mortal Wkly Rep 2009; 58(33): 913–8Google Scholar
  10. 10.
    Centers for Disease Control and Prevention (CDC). Hospitalized patients with novel influenza A (H1N1) virus infection: California, April–May, 2009. MMWR Morb Mortal Wkly Rep 2009; 58(19): 536–41Google Scholar
  11. 11.
    Chowell G, Bertozzi SM, Colchero MA, et al. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N Engl J Med 2009; 361(7): 674–9PubMedCrossRefGoogle Scholar
  12. 12.
    Perez-Padilla R, de de la Rosa-Zamboni D, Ponce de Leon S, et al. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med 2009; 361(7): 680–9PubMedCrossRefGoogle Scholar
  13. 13.
    Vaillant L, La RG, Tarantola A, et al. Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveill 2009; 14(33): pii: 19309Google Scholar
  14. 14.
    World Health Organization (WHO). Human infection with pandemic A (H1N1) 2009 influenza virus: clinical observations in hospitalized patients, Americas, July 2009 — update. Wkly Epidemiol Rec 2009; 84(30): 305–8Google Scholar
  15. 15.
    Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009; 374(9688): 451–8PubMedCrossRefGoogle Scholar
  16. 16.
    World Health Organization (WHO). WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses [online]. Available from URL: http://www.who.int/entity/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf [Accessed 2009 Sep 1]
  17. 17.
    Centers for Disease Control and Prevention (CDC). Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009–2010 season [online]. Available from URL: http://www.cdc.gov/h1n1flu/recommendations.htm[Accessed 2009 Sep 15]
  18. 18.
    European Medicines Agency (EMEA). EMEA updates on A/H1N1 influenza virus. Update on 31 July 2009 [online]. Available from URL: http://www.ema.europa.eu/humandocs/PDFs/EPAR/tamiflu/28766209en.pdf [Accessed 2010 Jun 1]
  19. 19.
    Ventura SJ, Abma JC, Mosher WD, et al. National vital statistics report: estimated pregnancy rates by outcome for the United States, 1990–2004 [online]. Available from URL: http://www.cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_15.pdf[Accessed 2010 May 4]
  20. 20.
    Cunningham FG, Levono KJ, Bloom SL, et al. Abortion. In: Seils A, Edmonson KG, Davis K, editors. Williams obstetrics. New York: McGraw-Hill, 2005: 231–51Google Scholar
  21. 21.
    Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2006. Natl Vital Stat Rep 2009; 57(7): 1–102Google Scholar
  22. 22.
    Cunningham FG, Leveno KJ, Bloom SL, et al. Preterm birth. In: Seils A, Edmonson KG, Davis K, editors. Williams obstetrics. New York: McGraw-Hill, 2005: 855–88Google Scholar
  23. 23.
    Centers for Disease Control and Prevention (CDC). Update on overall prevalence of major birth defects: Atlanta, Georgia, 1978–2005. MMWR Morb Mortal Wkly Rep 2008; 57: 1–5Google Scholar
  24. 24.
    FDA. FDA reviewer guidance: evaluating the risks of drug exposure in human pregnancies 2005 [online]. Available from URL: http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UCM133359.pdf [Accessed 2010 Jun 1]
  25. 25.
    Irving WL, James DK, Stephenson T, et al. Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. BJOG 2000; 107(10): 1282–9PubMedCrossRefGoogle Scholar
  26. 26.
    Neuzil KM, Reed GW, Mitchel EF, et al. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998; 148(11): 1094–102PubMedCrossRefGoogle Scholar
  27. 27.
    Le S, Rubio ER, Alper B, et al. Respiratory complications of pregnancy. Obstet Gynecol Surv 2002; 57(1): 39–46CrossRefGoogle Scholar
  28. 28.
    Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic influenza and pregnant women. Emerg Infect Dis 2008; 14(1): 95–100PubMedCrossRefGoogle Scholar
  29. 29.
    Cunningham FG, Leveno KJ, Bloom SL, et al. Maternal physiology. In:Seils A, Edmonson KG, Davis K, editors. Williams obstetrics. New York: McGraw-Hill, 2005: 121–50Google Scholar
  30. 30.
    Centers for Disease Control and Prevention (CDC). Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009; 58(RR-10): 1–8Google Scholar
  31. 31.
    European Centre for Disease Prevention and Control (ECDC). ECDC interim guidance: use of specific pandemic influenza vaccines during the H1N1 2009 pandemic [online]. Available from URL: http://ecdc.europa.eu/en/publications/Publications/0908_GUI_Pandemic_Influenza_Vaccines_during_the_H1N1_2009_Pandemic.pdf [Accessed 2010 May 4]
  32. 32.
    Hardy JMB, Azarowicz EN, Mannini A, et al. The effect of Asian influenza on the outcome of pregnancy, Baltimore, 1957–1957. Am J Public Health Nations Health 1961; 51(8): 1182–8PubMedCrossRefGoogle Scholar
  33. 33.
    Cox S, Posner SF, McPheeters M, et al. Hospitalizations with respiratory illness among pregnant women during influenza season. Obstet Gynecol 2006; 107(6): 1315–22PubMedCrossRefGoogle Scholar
  34. 34.
    Acs N, Banhidy F, Puho E, et al. Pregnancy complications and delivery outcomes of pregnant women with influenza. J Matern Fetal Neonatal Med 2006; 19(3): 135–40PubMedCrossRefGoogle Scholar
  35. 35.
    Griffiths PD, Ronalds CJ, Heath RB. A prospective study of influenza infections during pregnancy. J Epidemiol Community Health 1980; 34(2): 124–8PubMedCrossRefGoogle Scholar
  36. 36.
    Lynberg MC, Khoury MJ, Lu X, et al. Maternal flu, fever, and the risk of neural tube defects: a population-based case-control study. Am J Epidemiol 1994; 140(3): 244–55PubMedGoogle Scholar
  37. 37.
    Saxen L, Holmberg PC, Kurppa K, et al. Influenza epidemics and anencephaly. Am J Public Health 1990; 80(4): 473–5PubMedCrossRefGoogle Scholar
  38. 38.
    Gu J, Xie Z, Gao Z, et al. H5N1 infection of the respiratory tract and beyond: a molecular pathology study. Lancet 2007; 370(9593): 1137–45PubMedCrossRefGoogle Scholar
  39. 39.
    Meyer U, Feldon J, Fatemi SH. In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neurosci Biobehav Rev 2009 Jul; 33(7): 1061–79PubMedCrossRefGoogle Scholar
  40. 40.
    Edwards MJ. Review: Hyperthermia and fever during pregnancy. Birth Defects Res A Clin Mol Teratol 2006; 76(7): 507–16PubMedCrossRefGoogle Scholar
  41. 41.
    Jones KL. Smith’s recognizable patterns of human malformation. 6th ed. Philadelphia (PA): WB Saunders, 2006Google Scholar
  42. 42.
    Tikkanen J, Heinonen OP. Maternal hyperthermia during pregnancy and cardiovascular malformations in the offspring. Eur J Epidemiol 1991; 7(6): 628–35PubMedCrossRefGoogle Scholar
  43. 43.
    Acs N, Banhidy F, Puho E, et al. Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol 2005; 73(12): 989–96PubMedCrossRefGoogle Scholar
  44. 44.
    Czeizel AE, Puho EH, Acs N, et al. Delineation of a multiple congenital abnormality syndrome in the offspring of pregnant women affected with high fever-related disorders: a population-based study. Congenit Anom (Kyoto) 2008; 48(4): 158–66CrossRefGoogle Scholar
  45. 45.
    Data on file, RocheGoogle Scholar
  46. 46.
    Worley KC, Roberts SW, Bawdon RE. The metabolism and transplacental transfer of oseltamivir in the ex vivo human model. Infect Dis Obstet Gynecol 2008; 2008: 927574PubMedCrossRefGoogle Scholar
  47. 47.
    Ose A, Kusuhara H, Yamatsugu K, et al. P-glycoprotein restricts the penetration of oseltamivir across the blood-brain barrier. Drug Metab Dispos 2008; 36(2): 427–34PubMedCrossRefGoogle Scholar
  48. 48.
    Young AM, Allen CE, Audus KL. Efflux transporters of the human placenta. Adv Drug Deliv Rev 2003; 55(1): 125–32PubMedCrossRefGoogle Scholar
  49. 49.
    Gray RH, Wu LY. Subfertility and risk of spontaneous abortion. Am J Public Health 2000; 90(9): 1452–4PubMedCrossRefGoogle Scholar
  50. 50.
    Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. BMJ 1997; 315(7099): 32–4PubMedCrossRefGoogle Scholar
  51. 51.
    Moore KL, Persaud TVN. The developing human: clinically oriented embryology. 6th ed. Philadelphia (PA): WB Saunders, 1998: 548Google Scholar
  52. 52.
    de Haan TR, Oepkes D, Beersma MF, et al. Aetiology, diagnosis and treatment of hydrops foetalis. Curr Pediatr Rev 2005; 1: 63–72CrossRefGoogle Scholar
  53. 53.
    Arneja JS, Gosain AK. Giant congenital melanocytic nevi. Plast Reconstr Surg 2007; 124 (1 Suppl.): 1–13eGoogle Scholar
  54. 54.
    Hassold TA, Jacobs PA. Trisomy in man. Annu Rev Genet 1984; 18: 69–97PubMedCrossRefGoogle Scholar
  55. 55.
    Hayashi H, Yamane R, Tanaka M, et al. Pregnancy outcome after maternal exposure to oseltamivir phosphate during the first trimester: a case series survey. J Jpn Soc Hosp Pharm 2009; 45(4): 547–50Google Scholar
  56. 56.
    Tanaka T, Nakajima K, Murashima A, et al. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ 2009; 181(1–2): 55–8PubMedGoogle Scholar
  57. 57.
    Mastroianni MC, Faden R, Federman D. Risks to reproduction and offspring. In: Mastroianni MC, Faden R, Federman D, editors. Women and health research: ethical and legal issues of including women in clinical trials. Washington, DC: National Academy of Science Press, 1994: 175–202Google Scholar
  58. 58.
    Reller MD, Strickland MJ, Riehle-Colarusso T, et al. Prevalence of congenital heart defects in metropolitan Atlanta, 1998–2005. J Pediatr 2008; 153(6): 807–13PubMedCrossRefGoogle Scholar
  59. 59.
    Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis 2007; 2: 47PubMedCrossRefGoogle Scholar
  60. 60.
    Bar-Oz B, Moretti ME, Mareels G, et al. Reporting bias in retrospective ascertainment of drug-induced embryopathy. Lancet 1999; 354(9191): 1700–1PubMedCrossRefGoogle Scholar
  61. 61.
    Greer LG, Sheffield JS, Rogers VL, et al. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet Gynecol 2010; 115: 711–6PubMedCrossRefGoogle Scholar
  62. 62.
    Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010; 303: 1517–25PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Barbara Donner
    • 1
  • Viswanathan Niranjan
    • 2
  • Gerhard Hoffmann
    • 1
  1. 1.F. Hoffmann-La Roche LtdBaselSwitzerland
  2. 2.RxMDChennaiIndia

Personalised recommendations