Safety of Neuraminidase Inhibitors to Treat H1N1 Influenza During Pregnancy Reviewed CME/CE

News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD

June 23, 2009 —The safety of neuraminidase inhibitors for treatment of novel H1N1 influenza in pregnant and breast-feeding women is summarized in a review published in the June 15 Online First issue of the Canadian Medical Association Journal.

"A new strain of influenza A virus (novel influenza A H1N1) that originated in swine has rapidly spread from the initial outbreak in Mexico and the southern United States to Canada and many countries in Europe and Asia," write Toshihiro Tanaka, MD, from the Motherisk Program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children and University of Toronto in Toronto, Ontario, Canada, and colleagues.

"Consequently, the World Health Organization raised the level of alert for an influenza pandemic to 5 on Apr. 29, 2009. Because many infected people are young, the care of pregnant and lactating women is a concern."

The US Centers for Disease Control and Prevention states that H1N1 is susceptible to the neuraminidase-inhibitor antiviral medications oseltamivir and zanamivir, which target the early phase of influenza infection, but that this influenza strain is resistant to amantadine, rimantadine, and other adamantanes.

H1N1 Influenza Treatments

Especially during the third trimester, pregnant women are thought to be at high risk for complications from influenza, including mortality, although data are limited regarding the current novel H1N1 influenza A strain.

For pregnant women and others at high risk for complications, the Centers for Disease Control and Prevention currently recommends use of either oseltamivir or zanamivir for treatment and chemoprophylaxis against novel H1N1 influenza. Treatment should be started within 48 hours of the first influenza-related symptoms.

Using the MEDLINE database from 1950 to week 2 of May 2009 and EMBASE from 1980 to week 19 of 2009 through the OVID system, the reviewers searched the literature for reports of the use of oseltamivir or zanamivir during pregnancy, lactation, and breast-feeding. In addition, the reviewers collected pertinent data through the network of teratogen information services in Japan. Even before the current pandemic, the use of oseltamivir and zanamivir for patients with confirmed influenza was fairly common in Japan.

Limited evidence to date suggests that oseltamivir is not a major teratogen in humans. Because more data concerning the safety of use during pregnancy are available for oseltamivir vs zanamivir, use of oseltamivir in pregnant women is preferred vs use of zanamivir.

Both of these drugs are thought to be compatible with breast-feeding, and continuing breast-feeding when the mother is taking either medication is not likely to cause significant drug exposure in the infant. In fact, continuing breast-feeding is recommended even if the mother is being treated with oseltamivir and zanamivir because of the anti-infective benefits of human milk for infants.

Oseltamivir appears to be extensively metabolized by the placenta, but transplacental transfer of the metabolite is incomplete, with minimal accumulation on the fetal side. Postmarketing surveillance showed that of 61 pregnant women exposed to oseltamivir at unknown gestational time, 10 underwent abortion, including 6 therapeutic terminations, and 1 case each of trisomy 21 and anencephaly.

Similar Results in Japanese Study

Data from 2 Japanese teratogen information services yielded similar results. Among 90 pregnant women who took therapeutic doses of oseltamivir, there was 1 malformation (1.1%), which is not significantly different from the rate of major malformations within the general population (1% - 3%).

Safety data regarding exposure to zanamivir during pregnancy are extremely limited. During clinical trials, 3 pregnant women were unintentionally exposed to zanamivir; 1 of these pregnancies spontaneously miscarried, 1 was terminated, and 1 resulted in delivery of a healthy infant. One woman registered with the Japan Drug Information Institute in Pregnancy took zanamivir at 4 weeks of gestation and delivered a healthy infant at term.

Provided that contact between the mother and the infant is not contraindicated for other reasons, breast-feeding is permitted during treatment of the mother with oseltamivir or zanamivir, and dosage adjustment is not required. For breast-feeding infants of mothers receiving oseltamivir or zanamivir, the recommended dose of oseltamivir or zanamivir for infants should be given to those infants needing direct influenza treatment or chemoprophylaxis.

Infants exposed to oseltamivir or zanamivir during gestation or breast-feeding should be monitored and thoroughly observed, allowing prospective data collection regarding possible safety issues with these medications.

No Vaccine Available

"Currently no vaccine for novel H1N1 influenza exists," the review authors conclude. "However, vaccination for seasonal influenza should continue because of higher morbidity among pregnant women and possible concurrent epidemics with novel H1N1 influenza. Once developed, it is unlikely that an inactivated vaccine against novel H1N1 influenza would be contraindicated for pregnant and lactating women, similar to regular influenza vaccines."

The Japanese Ministry of Health, Labor and Welfare supports the Japan Drug Information Institute in Pregnancy, and the National Center for Child Health and Development–Motherisk Collaborative Research Fund supported this review. Some of the review authors have received support from Nobel Pharma Scholarship, TFB Scholarship, Scholarship for Researchers through the Japanese Society of Clinical Pharmacology and Therapeutics, The Research and Training Competition (RESTRACOMP) through the Hospital for Sick Children Research Institute, the Clinician Scientist Training Program funded by the Ontario Student Opportunity Trust Fund and the Hospital for Sick Children Foundation Student Scholarship Program, the Ivey Chair in Molecular Toxicology of the Department of Medicine at the University of Western Ontario, and/or the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation at The Hospital for Sick Children, Toronto, Ontario.

Can Med Assoc J. Published online June 15, 2009.

The US Centers for Disease Control and Prevention reports that groups at high risk for complications from novel influenza H1N1 virus include pregnant women. The recommended treatment and prophylaxis of the novel influenza H1N1 virus is neuraminidase inhibitors, including oseltamivir or zanamivir. However, adamantanes are not effective against this influenza strain, according to the May 1, 2009, issue of MMWR Morbidity and Mortality Weekly Report.

This review summarizes the safety of neuraminidase inhibitor treatment of novel influenza H1N1 virus in pregnant and breast-feeding women.

• A search of the literature identified studies of oseltamivir or zanamivir use during pregnancy, lactation, and breast-feeding through MEDLINE (1950 to week 2 of May 2009) and EMBASE (1980 to week 19 of 2009) databases.


• Additional information was obtained through the teratogen information services in Japan.


• Limited information about the transmission of influenza viruses through the placenta to the fetus is known.


• Influenza viruses are not considered teratogenic.


• Maternal influenza during pregnancy might have indirect teratogenic effects because of hyperthermia.


• Seasonal influenza has a higher morbidity risk in pregnant women, especially in the third trimester, vs nonpregnant and postpartum women.


• 20 pregnant women had recent infections of novel H1N1 influenza in the United States, including 15 confirmed cases: 3 were known to be hospitalized and 1 died of respiratory complications.


• The primary mode of influenza transmission is likely respiratory droplets.


• It is not known if influenza viruses pass into human milk.


• Oseltamivir is the preferred treatment or chemoprophylaxis in pregnant women because more safety data are available:




• Oseltamivir is hydrolyzed in the liver to oseltamivir carboxylate, its active metabolite.


• The elimination half-life is 6 to 10 hours.


• The therapeutic dose is 75 mg twice daily in adults and 2 mg/kg twice daily in children for 5 days, within 48 hours of initial symptoms.


• The chemoprophylaxis dose is 75 mg once daily in adults and 2 mg/kg once daily in children for 10 days.


• Of 61 pregnant women exposed to oseltamivir, 10 had abortions (6 therapeutic), 1 child had trisomy 21, and 1 child had anencephaly.


• Of 90 pregnant women in Japan who received oseltamivir treatment in the first trimester, 1 (1.1%) malformation occurred, similar to the 1% to 3% incidence in the general population.




• Zanamivir can be used for treatment or chemoprophylaxis of influenza H1N1, but safety data in pregnancy are limited:




• Administration by voluntary inhalation can be more difficult in young children.


• The elimination half-life is 2.5 to 5.1 hours.


• The therapeutic dose is 10 mg inhaled twice daily for 5 days, within 48 hours of initial symptoms for adults and children.


• The chemoprophylaxis dose is 10 mg inhaled once daily for 10 days.


• Of 4 pregnant women exposed to zanamivir, 1 spontaneously miscarried, 1 woman terminated pregnancy, and 2 women had healthy infants.




• Oseltamivir and zanamivir are compatible with breast-feeding.


• In a lactating woman receiving oseltamivir, the maximal levels were 38.2 ng/mL of oseltamivir and 39.5 ng/mL of its metabolite in milk, equivalent to 0.012 mg/kg/day in the infant.


• After zanamivir inhalation, the peak level is 34 to 96 ng/mL with an estimated equivalent of 0.075 mg/day in the breast-fed infant.


• Doses do not need to be adjusted in the mother or infant because of breast-feeding.


• Breast-fed infants should receive recommended doses for treatment or chemoprophylaxis if indicated, even if the mother is receiving oseltamivir or zanamivir.


• No vaccination is available for novel H1N1 influenza, but vaccination for seasonal influenza is recommended because of greater morbidity in pregnant women and the possibility of concurrent novel H1N1 influenza epidemics.

• In pregnant women at risk for novel influenza H1N1, the recommended treatment is oseltamivir.


• In breast-feeding women who need treatment of novel influenza H1N1, oseltamivir and zanamivir are compatible.