Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Limited reports describing the use of oseltamivir during human pregnancy do not suggest a significant risk of developmental toxicity. The drug is used for the treatment and prophylaxis of influenza, including novel influenza A (H1N1). Because influenza infection in pregnancy is a high-risk condition, the maternal benefit far outweighs the unknown risk, if any, to the embryo or fetus. Moreover, hyperthermia, a common condition of influenza infections, occurring during the 1st trimester doubles the risk of neural tube defects (1). In addition, maternal hyperthermia during labor is a risk factor for neonatal seizures, encephalopathy, cerebral palsy, and neonatal death. Thus, in either case, hyperthermia should be promptly treated with acetaminophen and, in the 1st trimester, combined with multivitamins containing folic acid (1).
FETAL RISK SUMMARY
Oseltamivir is an ethyl ester prodrug that is rapidly metabolized by hepatic esterases to oseltamivir carboxylate, the active antiviral agent. Systemic exposure to oseltamivir is <5% of the total exposure. It is a neuraminidase inhibitor in the same antiviral subclass as zanamivir. Plasma protein binding of oseltamivir carboxylate is low (3%), but the elimination half-life is prolonged (6–10 hours). Oseltamivir is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year of age and older who have been symptomatic for no more than 2 days. It also is indicated for the prophylaxis of influenza in patients aged 1 year and older (2). In April 2009, the FDA issued an Emergency Use Authorization to allow the drug to be used to treat and prevent influenza in children under 1 year of age, and to provide alternate dosing recommendations for children older than 1 year (3). Oseltamivir is active against novel influenza A (H1N1) (formerly known as swine flu), either as treatment of acute illness or as chemoprophylaxis in patients at high risk of complications, such as pregnant women (4).
In reproduction studies, doses up to 100 times the human systemic exposure based on AUC of oseltamivir carboxylate (HSE) had no effects on fertility or mating performance in male and female rats, or on embryo–fetal development. The highest dose was associated with minimal maternal toxicity. In rabbits, doses up to 50 times the HSE also had no effect on embryo–fetal development. Maternal toxicity was observed in rabbits with doses 15 times the HSE or higher. In both species, fetal exposure to the antiviral agent was documented. Although a dose-dependent increase in the incidence rates of skeletal abnormalities and variants was observed in both species, the individual incidence rate of each defect remained within the expected background rate of occurrence (2).
Oseltamivir and its active metabolite were not carcinogenic in 2-year studies in mice and rats. Oseltamivir was not mutagenic in several assays, but was positive in one. The active metabolite was negative in all assays (2).
Although the relatively low molecular weight (about 312 and 284 for the parent drug free base and metabolite, respectively), minimal plasma protein binding, and prolonged elimination half-life suggest that both the parent drug and the metabolite will cross to the embryo–fetus, a 2008 study (5) found otherwise. In the ex vivo human placenta model, extensive metabolism of oseltamivir to the active metabolite was observed, but neither the parent drug nor its metabolite could be detected on the fetal side when concentrations 5–6-fold above the therapeutic concentration were used. Concentrations 20–830-fold above the therapeutic range were required for detectable levels on the fetal side. The mean clearance index for these high levels was 0.13 and fetal accumulation was minimal (5).
The Centers for Disease Control and Prevention has published information on two cases of H1N1 virus infection in pregnancy that were treated with oseltamivir (4). A 29-year-old woman at 23 weeks’ gestation presented at a family practice clinic. She had a 1-day history of cough, sore throat, chills, fever, and weakness. Rapid influenza diagnostic testing was positive, and H1N1 virus was later confirmed. The mother was prescribed oseltamivir and her symptoms were resolving without complication. Her pregnancy was proceeding normally. The clinic physician who evaluated the mother was also pregnant (13 weeks’ gestation). She began prophylactic oseltamivir and had remained asymptomatic (4).
A 2005 report from the manufacturer briefly mentioned the use of oseltamivir in 61 pregnant women without specifying the timing of the exposures (6). Among these, there were four spontaneous abortions (SABs) and six elective abortions (EABs). In addition, there were single cases of trisomy 21 (Down’s syndrome) and anencephaly, neither of which was thought to be related to the drug therapy. The remaining cases resulted in the birth of normal infants (6).
A 2009 report summarized the safety of neuraminidase inhibitors in pregnant and breastfeeding women (7). The data, from two Japanese teratogen information services, involved 90 pregnancies exposed during the 1st trimester to therapeutic doses of oseltamivir (75 mg twice a day for up to 5 days). The outcomes of the pregnancies were three SABs, one EAB, four preterm births, seven infants with low birth weight, and one major malformation (ventricular septal defect). The malformation incidence (1.2%; 1 in 86 live births) is well within the background incidence of major malformations (7).
A retrospective cohort study, covering the period 2003–2008, described 239 pregnancies that were treated with antiviral agents during pregnancy (8). Of these, 104 women received M2 ion channel inhibitors (rimantadine, amantadine, or both) and 135 received oseltamivir. The pregnancy outcomes of these patients were compared with 82,097 controls from the site’s overall obstetric patient population. The exposure timing for the combined treated groups was 13% 1st trimester, 32% 2nd trimester, and 55% 3rd trimester. There were no significant differences between the treated groups and controls in terms of maternal and delivery characteristics except that M2 inhibitors had more multiple gestations. For M2 inhibitors, oseltamivir vs. controls, there also was no differences in stillbirths (0%, 0% vs. 1%), major defects (1% [trisomy 21], 0% vs. 2%), and minor defects (19%, 15% vs. 22%). The only significant finding in the characteristics of liveborn, singleton neonates, after exclusion of twins and major anomalies, was a higher risk of necrotizing enterocolitis in both treatment groups compared with controls—1.0%, 0.8% vs. 0.02% (8).
BREASTFEEDING SUMMARY
Oseltamivir and its active metabolite are excreted into breast milk. A woman who was breastfeeding her 9-month-old child twice daily accidentally stuck herself with a novel influenza A (H1N1)-contaminated needle (9). She was treated with oseltamivir 75 mg twice daily for 5 days. Breastfeeding was stopped during this period because of possible adverse effects in the infant. Milk samples (N = 11) were collected twice daily over the 5-day period by completely emptying both breasts. The timings of the samples were distributed at various times, with eight of the samples collected 30 minutes before or after a dose. The steady state concentration of the metabolite (37–39 ng/mL) was reached after 3 days. The authors estimated that the maximum relative infant dose (oseltamivir plus the metabolite) was 0.012 mg/kg/day or about 0.5% of the mother’s weight-adjusted dose (based on an assumed maternal weight of 60 kg) (9).
Based on the above study, in which the infant did not nurse, the concentration of the drug in breast milk appears to be clinically insignificant. In addition, the potential dose for a nursing infant is much less than the pediatric dose. Moreover, breastfeeding is recommended for women infected with novel influenza A (H1N1), regardless of whether they are being treated, because of the advantages of breast milk for the infant’s immune system (10).
References
1.Rasmussen SA, Jamieson DJ, MacFarlane K, Cragan JD, Williams J, Henderson Z, for the Pandemic Influenza Pregnancy Working Group. Pandemic influenza and pregnant women: summary of a meeting of experts. Am J Public Health 2009;99(Suppl 2):S248–54.
2.Product information. Tamiflu. Roche Laboratories, 2008.
3.FDA News Release. FDA authorizes emergency use of influenza medicines, diagnostic test in response to swine flu outbreak in humans. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149571.htm. Accessed June 8, 2009.
4.Centers for Disease Control and Prevention (CDC). Novel influenza A (H1N1) virus infections in three pregnant women—United States, April–May 2009. MMWR Morb Mortal Wkly Rep 2009 May 15;58(18): 497–500.
5.Worley KC, Roberts SW, Bawdon RE. The metabolism and transplacental transfer of oseltamivir in the ex vivo human model. Inf Dis Obstet Gynecol 2008;2008(Article ID 927574):1–5.
6.Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005;55(Suppl S1):i5–i21.
7.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;181:55–8.
8.Greer LG, Sheffield JS, Rogers VL, Roberts SW, McIntire DD, Wendel GD Jr. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet Gynecol 2010;115:711–6.
9.Wentges-van Holthe N, van Eijkeren M, van der Laan JW. Oseltamivir and breastfeeding. Int J Infect Dis 2008;12:451.
10.CDC. What pregnant women should know about H1N1 (formerly called swine flu) virus. Available at: http://www.cdc.gov/h1n1flu/guidance/pregnant.htm. Accessed June 8, 2009.