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Drugs, chemicals, radiation & herbal products in pregnancy: H1N1 Influenza in Pregnancy: Risks, vaccines and antivirals

Toronto, October 30, 2009 - The novel H1N1 influenza A virus has been shown to attack pregnant women more seriously. It is imperative to vaccinate expecting mothers. Unvaccinated pregnant women in contact with H1N1 should receive prophylactic antivirals. Limited existing information on the safety of oseltamivir and zanamivir is reassuring.

H1N1 Influenza

In April 2009 a novel influenza A virus (H1N1) was determined to be the cause of outbreaks of respiratory illness in Mexico (1). On April 26, Canada reported its first six cases of H1NI Flu Virus (2). In June 2009 the World Health Organization (WHO) declared the H1N1 influenza a pandemic due to confirmed cases seen around the world, with pregnant women being one of the groups stated to have an increased risk for complications (3). Pregnant women with seasonal influenza infection have been described to have a higher risk for complications than the general population in several studies (4, 5, 6). These same risks have been reported in women with H1N1 influenza. In a report by the Public Health Agency of Canada (PHAC), when compared to non-pregnant women and to people in general who contracted 2009 H1N1 influenza, pregnant women with 2009 H1N1 flu were more likely to be admitted to hospitals, have serious illness and death, and tended to have less medical conditions prior to their influenza illness. Also, pregnant women were reported to have a greater chance for pregnancy complications, such as miscarriage or premature delivery, with greater risk seen with those in the second half of pregnancy and the greatest risk seen in women in their third trimester (7). The increased risk of complications is thought to be related to physiologic changes that occur during pregnancy including alterations in immune, cardiovascular and respiratory system (8). In a report by the Centers for Disease Control and Prevention (CDC) summarizing cases of infection with H1N1 virus in pregnant women in the USA, pregnant women were four times more likely to be admitted to the hospital. Also, 13% of deaths were pregnant women, who were fairly healthy before their influenza illness (9).

H1N1 Influenza Vaccine

The World Health Organization (WHO), PHAC and CDC are recommending that pregnant women receive the H1N1 vaccine (10, 11, 12). Although studies on the safety of 2009 H1N1 flu vaccine have not been conducted on pregnant women, the seasonal flu vaccine has been given to millions of pregnant women over many years. Influenza vaccines have not been shown to cause harm to pregnant women or their babies (13). Also, the 2009 H1N1 flu vaccines are produced in a similar manner as the seasonal influenza vaccine. Therefore, the 2009 H1N1 influenza vaccines are expected to have similar safety profiles as seasonal flu vaccines (10).

Benefits have been seen in women and their infants after influenza vaccination during pregnancy. In a study from Bangladesh, immunization of women in their third trimester was found to reduce the incidence of febrile respiratory illness in both mother and her child when compared to women who received a pneumoccal vaccine during third trimester. Also, laboratory confirmed influenza febrile was reduced by 63% in their infants up to 6 months of age. (14)

Adjuvanted and Unadjuvanted:
There will be two types of H1N1 influenza vaccines available in Canada: adjuvanted and unadjuvanted. The adjuvanted vaccine is intended to increase an individual's immune response to the vaccine and allows for smaller doses of the virus antigen to be used in production while providing comparable immunogenicity to a non-adjuvanted vaccine. Adjuvanted vaccines are included in common vaccines such as tetanus and hepatitis B. The adjuvant, ASO3, in Canada's H1N1 influenza vaccine is made up of three ingredients: squalene, a natural, biodegradable oil (10.69 mg), DL-a-tocopherol (vitamin E oil, 11.86 mg), and polysorbate 80 (Tween 80), an emulsifier (4.86 mg). Clinical research trials using this adjuvant have been conducted in Canada, the U.S., and Europe demonstrating the safety of ASO3 containing vaccines (10). Although concerns are not expected with exposure to an adjuvanted H1N1 vaccine during pregnancy, the WHO states that the unadjuvanted vaccine is the preferred vaccine for pregnant women due to the extensive experience with unadjuvanted vaccines in pregnancy. However, if the unadjuvanted vaccine is not available and there is active H1N1 flu in the community then the adjuvanted vaccine should be offered to all pregnant women (15). Also, Health Canada states that only women who are more than 20 weeks of pregnancy or women who have a medical condition regardless of the stage of pregnancy should be offered the adjuvanted vaccine (10).

Thimerosal:
Thimerosal is a form of mercury used in the H1N1 flu vaccine to stabilize and maintain its quality during storage. Both the adjuvanted and unadjuvanted H1N1 vaccines contain small amounts of thimerosal, 5 microgram and 50 microgram respectively (16). To put it in perspective, a 170g can of tuna contains approximately 23.8- 61.2 microgram of methylmercury (17). There is no evidence that thimerosal is harmful to a pregnant woman or her child. Large cohort studies have demonstrated that there is no association with adverse neurodevelopmental outcomes, including autistic-spectrum disorders with children vaccinated with thimerosal containing vaccines (18). There have not been studies conducted examining the safety of exposure to thimerosal containing vaccines in pregnancy; however thimerosal containing influenza vaccines have been used in pregnant women for years and adverse effects have not been reported (10).

Breastfeeding:
The Advisory Committee for Immunization Practice state that neither inactive nor active vaccines are contraindicated during breastfeeding. Vaccines given to nursing women have not adversely affected mother or her infant (19).

Infants 0 to 59 months old, particularly those less than 24 months old, are considered to have a high risk for hospitalization from the H1N1 influenza. Therefore, individuals who are potentially capable of transmitting influenza to those at high risk should be immunized, regardless of whether the high-risk person has been immunized. Although there are no recommendations on the use of the H1N1 influenza vaccine specifically for nursing mothers, since they provide care for infants in the high risk group, breastfeeding mothers would be considered high priority individuals for vaccination with the H1N1 vaccine in order to protect their health and the health of their infants (10, 11).

Antiviral Medications

The 2009 H1N1 influenza virus is susceptible to the neuraminidase inhibitor antiviral medications, oseltamivir and zanamivir (20, 21). Although clinical data on the use of these and other antivirals during pregnancy is limited, pregnancy is not a contraindication to oseltamivir or zanamivir use (22, 23). A recently published review article reports that oseltamivir and zanamivir are relatively safe drugs for use in pregnant and breastfeeding women (24). The review reports on data from two Japanese teratogen information services that found no increased risk for birth defects among 90 pregnant women exposed to oseltamivir (75 mg twice daily for up to five days) during the first trimester. In these 90 cases, there was one (1.1%) malformation, (ventricular septal defect). This is within the incidence of major malformations in general population (1%-3%). The miscarriage rate was 3.3%, which is lower than in general population, and four (4.4%) babies were premature. There are fewer data available on zanamivir. In one report, among three pregnancies that included zanamivir exposure one pregnancy resulted in a healthy baby, one pregnancy was terminated, and one spontaneously miscarried (25).

The CDC updated interim recommendations for the use of antiviral medications indicate that pregnant women and women up to two weeks postpartum with suspected or confirmed influenza should receive prompt empiric antiviral therapy (22). Oseltamivir is given orally and results in systemic absorption; by contrast, zanamivir is given by inhalation and results in lower systemic absorption. Oseltamivir is preferred for treatment of pregnant women because of its systemic activity. Recommended treatment regimen is the same as those recommended for adults who have seasonal influenza, i.e. oseltamivir 75 mg twice daily for five days, or zanamivir 10 mg (two 5-mg inhalations) twice daily for five days. Antiviral treatment should be initiated as soon as possible after the onset of influenza symptoms, with benefits expected to be greatest if started within 48 hours of onset, based on data from studies of seasonal influenza (26). However, data from studies on seasonal influenza indicate benefit for hospitalized patients even if treatment is started more than 48 hours after onset. Regarding the drug of choice for chemoprophylaxis, zanamivir may be preferable because of its limited systemic absorption. However, respiratory complications that may be associated with zanamivir because of its inhaled route of administration need to be considered, especially in women at risk for respiratory problems (22). For these reasons and because of more available safety data, oseltamivir is a reasonable alternative. Recommended chemoprophylaxis is 75 mg oseltamivir once per day for 10 days, or 10 mg (two 5-mg inhalations) zanamivir once daily for 10 days after the last known exposure to H1N1 influenza virus. In addition to specific antiviral medication, acetaminophen should be given if the patient is febrile.

Antivirals and breastfeeding:
Use of antiviral medications for H1N1 treatment or chemoprophylaxis should not be a contraindication to breastfeeding. A recent paper reported on a nursing mother who was given oseltamivir 75 mg by mouth twice daily for five days (27). The dose in milk corresponded to 0.5% of the mother's weight-adjusted dosage. The authors calculated that the infant would receive 0.012 mg/kg daily which is much smaller than the pediatric doses (2 - 4 mg/kg daily). This dose is unlikely to cause any adverse effects in breastfed infants.

Zanamivir has poor systemic absorption, and it is not likely to reach the bloodstreem of the infant in clinically relevant amounts. A group of authors estimated that an exclusively breastfed 5 kg infant would receive about 0.075 mg daily in breastmik after an inhaled maternal dose of 10 mg, which is less then 1% of the recommended prophylactic dose for children (24).

Conclusion

Pregnant women are recommended to receive the unadjuvanted H1N1 vaccine. However adjuvanted H1N1 vaccine is not expected to be a concern. Therefore, if there is active H1N1 influenza in the community and unadjuvanted vaccine is unavailable then pregnant women and their health care providers should consider the adjuvanted H1N1 vaccine because pregnant women, especially those in their second half of pregnancy are at increased risk for health and pregnancy complications. Also, nursing women should be vaccinated with the adjuvanted H1N1 vaccine in order to protect themselves and their infants.

For treatment or chemoprophylaxis during the current H1N1 influenza infection, oseltamivir appears to be the drug of choice because there is more data on its safety in pregnancy. Zanamivir can be used, although there is less data available about its safety in pregnant women. Neither drug appears to affect the growth and development of the fetus, although ongoing data collection is important. Both oseltamivir and zanamivir are considered to be compatible with breastfeeding.

References

  1. Centers for Disease Control and Prevention. Outbreak of swine-origin influenza A (H1N1) virus infection - Mexico, March-April 2009. MMWR 2009;58:467-70.
  2. Public Health Agency of Canada. FluWatch Weekly Report Apr 19-Apr 25, 2009 (Week 16). Available at: http://www.phac-aspc.gc.ca/fluwatch/08-09/w16_09/index-eng.php, Accessed October 27, 2009.
  3. Zarocostas J. World Health Organization declares A (H1N1) influenza pandemic BMJ June 12 2009;338:b2425.
  4. Schanzer DL, Langley JM, Tam TW. Influenza-attributed hospitalization rates among pregnant women in Canada 1994-2000. J Obstet Gynaecol Can Aug 2007;29:622-9.
  5. Tuyishime JD, De Wals P, Moutquin JM et al. Influenza-like illness during pregnancy: results from a study in the eastern townships, province of Quebec. J Obstet Gynaecol Can 2003;25:1020-5.
  6. Dodds L, McNeil SA, Fell DB, et al. Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women. CMAJ. 2007;176(4):463-8.
  7. Public Health Agency of Canada. Flu Watch: Oct 11, 2009 to October 17, 2009 (Week 41). Available at http://www.phac-aspc.gc.ca/fluwatch/09-10/w41_09/index-eng.php. Accessed October 26, 2009.
  8. Jamieson DJ, Theiler RN, Rasmussen SA. Emerging infections and pregnancy. Emerg Infect Dis. 2006;12(11):1638-43.
  9. Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009;374:451--8.
  10. Public Health Agency of Canada. Guidance Document on the Use of Pandemic Influenza A (H1N1) 2009 Inactivated Monovalent Vaccine October 21, 2009. Available at http://www.phac-aspc.gc.ca/alert-alerte/h1n1/vacc/pdf/monovacc-guide-eng.pdf. Accessed October 28, 2009.
  11. CDC. Use of Influenza A (H1N1) 2009 Monovalent Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009 MMWR 2009;58(No. RR-10) :1-8. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5810a1.htm. Accessed October 23, 2009.
  12. World Health Organization. WHO recommendations on pandemic (H1N1) 2009 vaccines Available at http://www.who.int/csr/disease/swineflu/notes/h1n1_vaccine_20090713/en/index.html. Accessed October 29, 2009.
  13. Heinonen OP, Shapiro S, Monson RR, Hartz SC, Rosenberg L, Slone D. Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy. Int J Epidemiol 1973;2:229-35.
  14. Zaman K, Roy E, Arifeen SE, et al. Effectiveness of maternal influenza immunization in mothers and infants. New Engl J Med 2008; 359: 1555-64.
  15. World Health Organization. Strategic advisory group of experts on immunization--report of the extraordinary meeting on the influenza A (H1N1) 2009 pandemic, 7 July 2009. Wkly Epidemiol Rec 2009;84(30):301-4.
  16. Public Health Agency of Canada. Frequently Asked Questions - H1N1 Flu Virus Available at http://www.phac-aspc.gc.ca/alert-alerte/h1n1/faq_rg_h1n1-eng.php#vs. Accessed October 26, 2009.
  17. Health Canada. Human Health Risk Assessment of Mercury in Fish and Health Benefits of Fish Consumption. Available at http://www.hc-sc.gc.ca/fn-an/pubs/mercur/merc_fish_poisson-eng.php. Accessed Oct 29, 2009.
  18. Gerber JS, Offit PA. Vaccines and autism: a tale of shifting hypotheses. Clin Infect Dis 2009;48:456-61.
  19. Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-15):1-48.
  20. Centers for Disease Control and Prevention. Update: drug susceptibility of swine origin influenza A (H1N1) viruses, April 2009. MMWR Morb Mortal Wkly Rep 2009;58:433-5.
  21. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360(25):2605-15.
  22. Centers for Disease Control and Prevention: Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season. October 16, 2009 4:00 PM ET. Available at http://www.cdc.gov/H1N1flu/recommendations.htm. Accessed October 28, 2009.
  23. Centers for Disease Control and Prevention: Pregnant Women and Novel Influenza A (H1N1) Virus: Considerations for Clinicians June 30, 2009 10:19 AM ET Available at http://www.cdc.gov/h1n1flu/clinician_pregnant.htm. Accessed October 28, 2009.
  24. Tanaka T, Nakajima K, Murashima A, Garcia-Bournissen F, Koren G, Ito S. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ 2009;181(1-2):55-8.
  25. Freund B, Gravenstein S, Elliott M, Miller I: Zanamivir: review of clinical safety. Drug Saf 1999;21:267-281.
  26. Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep. 2008 Aug 8;57(RR-7):1-60.
  27. Wentges-van Holthe N, van Eijkeren M, van der Laan JW. Oseltamivir and breastfeeding. Int J Infect Dis. 2008;12:451.
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