tetano
Editor, Senior Moderator
Editorial | July 11, 2012
Influenza Pandemics?Pregnancy, Pathogenesis, and Perinatal Outcomes
Mark C. Steinhoff, MD; Noni E. MacDonald, MD, MSc, FRCPC
[+] Author Affiliations
JAMA. 2012;308(2):184-185. doi:10.1001/jama.2012.7911
Since the 1918 influenza pandemic, it has been clear that pandemic influenza is associated with increased morbidity and mortality in pregnancy, and more recent studies have shown that nonpandemic seasonal influenza strains also lead to morbidity for pregnant women and their infants.1 In the 2009 worldwide pandemic of influenza A(H1N1)pdm09, pregnant women were at high risk for severe complications, including death and intensive care unit admission.2
The adverse effects of antenatal influenza infection on pregnant women and their infants suggest a biological effect of influenza infection in the mother that compromises the fetus. These effects are rarely associated with direct infection of the fetus with influenza virus, although fetal infection has been reported infrequently during epidemics, pandemics,3 - 4 and with the H5N1 influenza strain.5 Instead, it appears that the normal pregnancy-associated immunologic changes may inhibit the inflammatory response to influenza virus infection in pregnancy,6 leading to increased risks to mother and infant. Because of these observations, pregnant women have been listed among high-risk groups for seasonal influenza vaccine in the United States since 1997, and safety data suggest these vaccines are safe in pregnancy.7 - 8 Pregnant women were prioritized for immunization during the 2009 influenza A(H1N1)pdm09 pandemic, despite limited data on the safety of pandemic influenza vaccines in pregnancy.
In this issue of JAMA, Pasternak and colleagues9 report the results of an observational cohort study on the safety in pregnancy of the monovalent inactivated ASO3-adjuvanted split virion influenza A(H1N1)pdm09 vaccine. The authors linked several Danish national registries to examine outcomes in infants born during the 2009 influenza A(H1N1)pdm09 pandemic. From a cohort of 53 432 infants, 6989 received the influenza vaccine during pregnancy. The authors included 330 infants whose mothers received the influenza A(H1N1)pdm09 vaccine in the first trimester and 6642 infants whose mothers received the vaccine in the second or third trimesters in propensity score analyses matched 1:1 with infants whose mothers were unvaccinated. No statistically significant relationships were found between receipt of vaccine and several perinatal outcomes, including major birth defects, preterm birth, and fetal growth restriction. The authors had sufficient sample size to exclude these adverse outcomes after vaccination in the second or third trimesters, but could only exclude moderate to large risks after vaccination in the first trimester. In addition, these authors recently reported on the risk of fetal death (spontaneous abortion and stillbirth) in the same cohort and found no increased risk after vaccination in pregnancy.10 These results suggest that this monovalent adjuvanted pandemic vaccine is safe when given during pregnancy.
The authors did not address the question of vaccine effectiveness and did not discuss the issue of narcolepsy, which was observed with use of this adjuvanted vaccine in Scandinavian countries.11 However, the researchers have the opportunity to follow up this cohort of children to determine long-term vaccine safety, ie, assessment of early infant development.
Recently, Fell et al12 reported a similar analysis of the use of H1N1 pdm09 adjuvanted vaccine in a cohort in Ontario, Canada, of 55 570 pregnant women, of whom 23 340 received the vaccine. This study demonstrated that mothers who were immunized were less likely than mothers who were not to have an infant with small for gestational age (relative risk [RR], 0.90; 95% CI, 0.85-0.96), preterm birth at less than 32 weeks gestation (RR, 0.73; 95% CI, 0.53-0.91), and fetal death (RR, 0.66; 95% CI, 0.47-0.91). Reports of maternal vaccination during seasonal influenza have also shown a reduction in the proportion of small for gestational age births and an increase in mean birth weight associated with immunization of the pregnant woman, or a decrease in birth weight related to influenza infection.13 - 14
The pandemic vaccine used in Denmark was an adjuvanted vaccine. In the United States, a nonadjuvanted vaccine was used during the 2009 pandemic with identical H1N1 viral antigens, which were also included in the seasonal trivalent vaccines for 2009-2012. Data from the United States suggest that vaccines without adjuvant containing pdm09 H1N1 antigens are safe.15
In addition to potential risks of the pandemic influenza vaccine to the fetus, other risks of influenza immunization for adults must also be considered. In this issue of JAMA, in a population-based cohort study (not specific to pregnant women) from October 2009 to March 2010 in Quebec, Canada, de Wals and colleagues16 identified a small, statistically significant risk of Guillain-Barr? syndrome during the 4 to 8 weeks after immunization with an H1N1 adjuvanted vaccine. The authors identified 83 confirmed cases of Guillain-Barr? syndrome, of which 25 confirmed cases had been vaccinated less than 8 weeks before disease onset. The authors estimated an RR for Guillain-Barr? syndrome of 1.80 (95% CI, 1.12-2.87), with the number of cases potentially attributable to vaccination at 2 per million doses, and found no indication of excess risk among those younger than 50 years.
Taken together, these studies partially assuage concerns about safety of adjuvanted pandemic influenza vaccines during pregnancy. However, more studies are needed examining other types of vaccine adjuvants. In addition, observational studies of vaccines are limited by biases, including selection bias, as well as confounding by indication. Thus, future studies with improved statistical designs including prospective follow-up studies using virological end points with adjustments for selection, seasonality, and other biases are needed to confirm these data.
Currently, protection of mothers and their infants against pandemic or seasonal influenza through immunization of pregnant women remains a key strategy. Development of improved treatment and prevention strategies will require evaluation of the mechanisms of the physiological alterations of the inflammatory response in normal pregnancy, investigation of the pathophysiology of the adverse clinical outcomes with influenza infection, and evaluation of the antibody response of pregnant and nonpregnant women to current inactivated influenza vaccines. Animal models of influenza in pregnancy can enhance our understanding of the pathophysiology and immunology in both the pregnant woman and the fetus.
Other possible approaches to prevention of influenza complications in pregnant women and their infants include antiviral treatment or prophylaxis with oseltamivir or zanamvir, which are currently recommended and were recommended for use during the 2009 pandemic.17 To date, no influenza vaccines are licensed for use in infants younger than 6 months. These infants are a reservoir for potential child-to-adult transmission. It is possible that immunization of pregnant women or women who have recently given birth may provide specific influenza protection for the young infant through breast milk, but this has not been fully evaluated.
Pandemic influenza has increased the attention of scientists, the public, and policy makers to influenza vaccine and its use in pregnancy. The hope is that such increased attention will translate into support for approaches to assessing the details of the altered immunology of pregnancy and of the pathophysiology of antenatal influenza infection, leading to effective prevention and treatment strategies for pregnant women and their infants.18
http://jama.jamanetwork.com/article.aspx?articleid=1216458
Influenza Pandemics?Pregnancy, Pathogenesis, and Perinatal Outcomes
Mark C. Steinhoff, MD; Noni E. MacDonald, MD, MSc, FRCPC
[+] Author Affiliations
JAMA. 2012;308(2):184-185. doi:10.1001/jama.2012.7911
Since the 1918 influenza pandemic, it has been clear that pandemic influenza is associated with increased morbidity and mortality in pregnancy, and more recent studies have shown that nonpandemic seasonal influenza strains also lead to morbidity for pregnant women and their infants.1 In the 2009 worldwide pandemic of influenza A(H1N1)pdm09, pregnant women were at high risk for severe complications, including death and intensive care unit admission.2
The adverse effects of antenatal influenza infection on pregnant women and their infants suggest a biological effect of influenza infection in the mother that compromises the fetus. These effects are rarely associated with direct infection of the fetus with influenza virus, although fetal infection has been reported infrequently during epidemics, pandemics,3 - 4 and with the H5N1 influenza strain.5 Instead, it appears that the normal pregnancy-associated immunologic changes may inhibit the inflammatory response to influenza virus infection in pregnancy,6 leading to increased risks to mother and infant. Because of these observations, pregnant women have been listed among high-risk groups for seasonal influenza vaccine in the United States since 1997, and safety data suggest these vaccines are safe in pregnancy.7 - 8 Pregnant women were prioritized for immunization during the 2009 influenza A(H1N1)pdm09 pandemic, despite limited data on the safety of pandemic influenza vaccines in pregnancy.
In this issue of JAMA, Pasternak and colleagues9 report the results of an observational cohort study on the safety in pregnancy of the monovalent inactivated ASO3-adjuvanted split virion influenza A(H1N1)pdm09 vaccine. The authors linked several Danish national registries to examine outcomes in infants born during the 2009 influenza A(H1N1)pdm09 pandemic. From a cohort of 53 432 infants, 6989 received the influenza vaccine during pregnancy. The authors included 330 infants whose mothers received the influenza A(H1N1)pdm09 vaccine in the first trimester and 6642 infants whose mothers received the vaccine in the second or third trimesters in propensity score analyses matched 1:1 with infants whose mothers were unvaccinated. No statistically significant relationships were found between receipt of vaccine and several perinatal outcomes, including major birth defects, preterm birth, and fetal growth restriction. The authors had sufficient sample size to exclude these adverse outcomes after vaccination in the second or third trimesters, but could only exclude moderate to large risks after vaccination in the first trimester. In addition, these authors recently reported on the risk of fetal death (spontaneous abortion and stillbirth) in the same cohort and found no increased risk after vaccination in pregnancy.10 These results suggest that this monovalent adjuvanted pandemic vaccine is safe when given during pregnancy.
The authors did not address the question of vaccine effectiveness and did not discuss the issue of narcolepsy, which was observed with use of this adjuvanted vaccine in Scandinavian countries.11 However, the researchers have the opportunity to follow up this cohort of children to determine long-term vaccine safety, ie, assessment of early infant development.
Recently, Fell et al12 reported a similar analysis of the use of H1N1 pdm09 adjuvanted vaccine in a cohort in Ontario, Canada, of 55 570 pregnant women, of whom 23 340 received the vaccine. This study demonstrated that mothers who were immunized were less likely than mothers who were not to have an infant with small for gestational age (relative risk [RR], 0.90; 95% CI, 0.85-0.96), preterm birth at less than 32 weeks gestation (RR, 0.73; 95% CI, 0.53-0.91), and fetal death (RR, 0.66; 95% CI, 0.47-0.91). Reports of maternal vaccination during seasonal influenza have also shown a reduction in the proportion of small for gestational age births and an increase in mean birth weight associated with immunization of the pregnant woman, or a decrease in birth weight related to influenza infection.13 - 14
The pandemic vaccine used in Denmark was an adjuvanted vaccine. In the United States, a nonadjuvanted vaccine was used during the 2009 pandemic with identical H1N1 viral antigens, which were also included in the seasonal trivalent vaccines for 2009-2012. Data from the United States suggest that vaccines without adjuvant containing pdm09 H1N1 antigens are safe.15
In addition to potential risks of the pandemic influenza vaccine to the fetus, other risks of influenza immunization for adults must also be considered. In this issue of JAMA, in a population-based cohort study (not specific to pregnant women) from October 2009 to March 2010 in Quebec, Canada, de Wals and colleagues16 identified a small, statistically significant risk of Guillain-Barr? syndrome during the 4 to 8 weeks after immunization with an H1N1 adjuvanted vaccine. The authors identified 83 confirmed cases of Guillain-Barr? syndrome, of which 25 confirmed cases had been vaccinated less than 8 weeks before disease onset. The authors estimated an RR for Guillain-Barr? syndrome of 1.80 (95% CI, 1.12-2.87), with the number of cases potentially attributable to vaccination at 2 per million doses, and found no indication of excess risk among those younger than 50 years.
Taken together, these studies partially assuage concerns about safety of adjuvanted pandemic influenza vaccines during pregnancy. However, more studies are needed examining other types of vaccine adjuvants. In addition, observational studies of vaccines are limited by biases, including selection bias, as well as confounding by indication. Thus, future studies with improved statistical designs including prospective follow-up studies using virological end points with adjustments for selection, seasonality, and other biases are needed to confirm these data.
Currently, protection of mothers and their infants against pandemic or seasonal influenza through immunization of pregnant women remains a key strategy. Development of improved treatment and prevention strategies will require evaluation of the mechanisms of the physiological alterations of the inflammatory response in normal pregnancy, investigation of the pathophysiology of the adverse clinical outcomes with influenza infection, and evaluation of the antibody response of pregnant and nonpregnant women to current inactivated influenza vaccines. Animal models of influenza in pregnancy can enhance our understanding of the pathophysiology and immunology in both the pregnant woman and the fetus.
Other possible approaches to prevention of influenza complications in pregnant women and their infants include antiviral treatment or prophylaxis with oseltamivir or zanamvir, which are currently recommended and were recommended for use during the 2009 pandemic.17 To date, no influenza vaccines are licensed for use in infants younger than 6 months. These infants are a reservoir for potential child-to-adult transmission. It is possible that immunization of pregnant women or women who have recently given birth may provide specific influenza protection for the young infant through breast milk, but this has not been fully evaluated.
Pandemic influenza has increased the attention of scientists, the public, and policy makers to influenza vaccine and its use in pregnancy. The hope is that such increased attention will translate into support for approaches to assessing the details of the altered immunology of pregnancy and of the pathophysiology of antenatal influenza infection, leading to effective prevention and treatment strategies for pregnant women and their infants.18
http://jama.jamanetwork.com/article.aspx?articleid=1216458