A review of fetal and infant protection associated with antenatal influenza immunization
2012; Elsevier BV; Volume: 207; Issue: 3 Linguagem: Inglês
10.1016/j.ajog.2012.06.071
ISSN1097-6868
AutoresMark C. Steinhoff, Saad B. Omer,
Tópico(s)Child and Adolescent Health
ResumoThe well-described burden of influenza morbidity in the pregnant woman and her young infant have led to increasing interest in the use of antenatal immunization to protect both the mother and the infant. In this review, we summarize the recent data on the effect of antenatal influenza infection, and influenza immunization, on mothers and infants. Antenatal influenza immunization can improve intrauterine growth in Asia and North America and reduce preterm deliveries. Studies of the pathogenetic process of influenza infection in the mother and fetus are needed. These findings suggest the wider use of antenatal immunization should be encouraged, including in low-resource regions. Creative approaches to antenatal influenza immunization policy should be developed to provide protection to the maternal, fetal, and infant triad in temperate and tropical regions. The well-described burden of influenza morbidity in the pregnant woman and her young infant have led to increasing interest in the use of antenatal immunization to protect both the mother and the infant. In this review, we summarize the recent data on the effect of antenatal influenza infection, and influenza immunization, on mothers and infants. Antenatal influenza immunization can improve intrauterine growth in Asia and North America and reduce preterm deliveries. Studies of the pathogenetic process of influenza infection in the mother and fetus are needed. These findings suggest the wider use of antenatal immunization should be encouraged, including in low-resource regions. Creative approaches to antenatal influenza immunization policy should be developed to provide protection to the maternal, fetal, and infant triad in temperate and tropical regions. The increased burden of influenza-associated morbidity in pregnant women has been well described, and national policy in several countries encourages influenza immunization to protect pregnant women.1Mak T.K. Mangtani P. Leese J. Watson J.M. Pfeifer D. Influenza vaccination in pregnancy: current evidence and selected national policies.Lancet Infect Dis. 2008; 8: 44-52Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Young infants 0-6 months of age have very high incidence of influenza infection. For example, during some winters in the United States, up to 1% of all infants are brought for medical care for influenza illness, including hospitalization.2Poehling K.A. Edwards K.M. Weinberg G.A. et al.The underrecognized burden of influenza in young children.N Engl J Med. 2006; 355: 31-40Crossref PubMed Scopus (739) Google Scholar Data are more limited in low-resource regions, but infants in the first 6 months of life in Bangladesh have been shown to be infected with influenza virus at a rate of 31 per 100 infants.3Henkle E. Steinhoff M.C. Omer S.B. et al.Incidence of influenza virus infection in early infancy: a prospective study in South Asia.Pediatr Infect Dis J. 2011; 30: 170-173Crossref PubMed Scopus (18) Google Scholar These high influenza burdens in the pregnant woman and her young infant have led to increasing interest in the use of antenatal immunization to protect both the mother and the infant. We briefly review the results from the randomized controlled trial of antenatal influenza vaccine in Bangladesh and summarize additional data from recent analyses of the effect of maternal antenatal influenza disease or immunization on the fetus. The Mother's Gift project was a randomized trial designed to assess the safety and immunogenicity of antenatal maternal influenza and pneumococcal vaccines in Bangladesh.4Zaman K. Roy E. Arifeen S.E. et al.Effectiveness of maternal influenza immunization in mothers and infants.N Engl J Med. 2008; 359: 1555-1564Crossref PubMed Scopus (971) Google Scholar The study was carried out from August 2004 through December 2005. We randomly assigned 340 healthy pregnant women in the third trimester to receive either trivalent inactivated influenza vaccine (Fluarix; 2004 Southern Hemisphere formulation; GlaxoSmithKline, Brentford, Middlesex, UK) or the 23 valent pneumococcal polysaccharide vaccine (Pneumovax 23; Merck, Whitehouse, NJ). The subjects were formally randomized, and families and staff were not aware of vaccine status. The subjects were interviewed at home each week from the time of immunization until 6 months after delivery; all episodes of respiratory illness were recorded. Infants with signs of respiratory infection and fever were tested with a rapid influenza antigen detection test. As reported, there was a 36% reduction of febrile illness with fever in the mothers and a 63% reduction of positive influenza test and 29% decrease in febrile illness in the infants of the mothers who received influenza vaccine.4Zaman K. Roy E. Arifeen S.E. et al.Effectiveness of maternal influenza immunization in mothers and infants.N Engl J Med. 2008; 359: 1555-1564Crossref PubMed Scopus (971) Google Scholar These data, showing effectiveness of antenatal influenza immunization on infant outcomes, were reported in 2008 and were considered by some of limited generalizability. Two earlier retrospective nonrandomized analyses of antenatal immunization had not shown effects on infant illness. The reports by Black et al5Black S.B. Shinefield H.R. France E.K. Fireman B.H. Platt S.T. Shay D. Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants.Am J Perinatol. 2004; 21: 333-339Crossref PubMed Scopus (162) Google Scholar in 2004 and France et al6France E.K. Smith-Ray R. McClure D. et al.Impact of maternal influenza vaccination during pregnancy on the incidence of acute respiratory illness visits among infants.Arch Pediatr Adolesc Med. 2006; 160: 1277-1283Crossref PubMed Scopus (93) Google Scholar in 2006 are similar in that each reported a retrospective analysis of the outcomes of antenatal influenza immunization in California. These retrospective nonrandomized studies had very low maternal immunization (0.7-20%) and influenza illness rates. As noted by the authors, these low rates limit the statistical power of the studies. The Black study had an extremely low rate of reported hospitalization among the mothers (18 of 100,000 pregnancies) and low rates of influenza-like illnesses (ILI) among the mothers and infants (36 and 420 of 100,000 subjects). This study showed no clinical effect at all of influenza vaccine, which is surprising, considering the numerous reports of clinical protection by vaccine in pregnancy. In addition, the paper by France et al was not able to gather data on important illness covariates including number of siblings in the home, parental smoking status, breastfeeding, and day care attendance. However, there have been several recent reports confirming a substantial effect of antenatal influenza immunization on infant outcomes (Table 1).TABLE 1Antenatal influenza immunization and infant outcomes at 0–6 monthsAuthorSiteDesignVaccineControlEffect in infantaExpressed as efficacy (percent reduction of infant outcome).Zaman et al, 20084Zaman K. Roy E. Arifeen S.E. et al.Effectiveness of maternal influenza immunization in mothers and infants.N Engl J Med. 2008; 359: 1555-1564Crossref PubMed Scopus (971) Google ScholarBangladesh, 2004–2005Randomized controlled trial of vaccine17216836% ILI 69% rapid test influenza illnessBenowitz et al, 20109Benowitz I. Esposito D.B. Gracey K.D. Shapiro E.D. Vazquez M. Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants.Clin Infect Dis. 2010; 51: 1355-1361Crossref PubMed Scopus (258) Google ScholarConnecticut, 2000–2009Case-control9115691.5% DFA or PCR influenza hospitalizationPoehling et al, 20118Poehling K.A. Szilagyi P.G. Staat M.A. et al.Impact of maternal immunization on influenza hospitalizations in infants.Am J Obstet Gynecol. 2011; 204: S141-S148Abstract Full Text Full Text PDF PubMed Scopus (203) Google ScholarTennessee, Ohio, New York, 2002–2009Case-control151135945–48% viral culture or PCR in influenza hospitalizationEick et al, 20117Eick A.A. Uyeki T.M. Klimov A. et al.Maternal influenza vaccination and effect on influenza virus infection in young infants.Arch Pediatr Adolesc Med. 2011; 165: 104-111Crossref PubMed Scopus (247) Google ScholarApache, Navajo, 2002-2005Observational prospective cohort57358741% serologically defined influenza episodeDFA, direct fluorescent antibody; ILI, influenza-like illness; PCR, polymerase chain reaction.Steinhoff. Antenatal influenza Immunization. Am J Obstet Gynecol 2012.a Expressed as efficacy (percent reduction of infant outcome). Open table in a new tab DFA, direct fluorescent antibody; ILI, influenza-like illness; PCR, polymerase chain reaction. Steinhoff. Antenatal influenza Immunization. Am J Obstet Gynecol 2012. Eick et al7Eick A.A. Uyeki T.M. Klimov A. et al.Maternal influenza vaccination and effect on influenza virus infection in young infants.Arch Pediatr Adolesc Med. 2011; 165: 104-111Crossref PubMed Scopus (247) Google Scholar conducted a nonrandomized, prospective, observational cohort study in the Navajo and Apache Indian reservations by following up 1169 mother-infant pairs from birth to 6 months over 3 influenza seasons from November 2002 to 2005. They compared the rates of laboratory-confirmed influenza illness in infants of mothers who received flu vaccine with rates in those who had not. The study showed a 41% reduction in the risk of laboratory-confirmed infant influenza infection, and a 39% reduction in clinical ILI hospitalizations. The New Vaccine Surveillance Network of the Centers for Disease Control and Prevention collects data through active hospital surveillance system in 3 counties in Tennessee, Ohio, and New York. Poehling et al8Poehling K.A. Szilagyi P.G. Staat M.A. et al.Impact of maternal immunization on influenza hospitalizations in infants.Am J Obstet Gynecol. 2011; 204: S141-S148Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar carried out a retrospective analysis of their data set of 2122 child hospitalizations during 7 winter influenza seasons from 2002 through 2009 to estimate the effect of antenatal influenza immunization on laboratory-proven influenza-associated hospitalization. They showed that 12% of the mothers of influenza-positive infants and 20% of the mothers of influenza-negative infants had received influenza vaccine, an odds ratio of 0.52 after adjustment. This multicenter and multiyear evaluation showed antenatal maternal immunization reduced the risk of infant influenza hospitalization by 45-48%. A case-control study from Connecticut by Benowitz et al9Benowitz I. Esposito D.B. Gracey K.D. Shapiro E.D. Vazquez M. Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants.Clin Infect Dis. 2010; 51: 1355-1361Crossref PubMed Scopus (258) Google Scholar assessed hospitalizations associated with laboratory-confirmed influenza in infants during the years 2000-2009. Their data showed 2.2% of 91 influenza-infected infants had mothers who had received antenatal influenza vaccine, compared with 19.9% of matched 156 control infants without influenza infection. This is a 90.7% adjusted effectiveness of antenatal influenza immunization in preventing 0-6 month infant influenza-associated hospitalizations. These 3 North American studies, which assess data from multiple states over periods of 3-9 influenza seasons, show clear infant protection associated with antenatal influenza immunization. The reported vaccine effects show disease reductions of 41-91%, reflecting the varying populations, attack rates, laboratory tests for influenza, and the annual variation of influenza virus and the composition of the vaccine. To summarize the data from the studies by Poehling et al8Poehling K.A. Szilagyi P.G. Staat M.A. et al.Impact of maternal immunization on influenza hospitalizations in infants.Am J Obstet Gynecol. 2011; 204: S141-S148Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar and Benowitz et al,9Benowitz I. Esposito D.B. Gracey K.D. Shapiro E.D. Vazquez M. Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants.Clin Infect Dis. 2010; 51: 1355-1361Crossref PubMed Scopus (258) Google Scholar the effect of influenza immunization reported in these 2 studies suggest that between 6 (95% confidence interval [CI], 4–9) and 20 (95% CI, 12–64) mothers need to be immunized to prevent 1 influenza-associated 0-6 month infant hospitalization. Five recent reports examined the fetal/newborn outcomes of antenatal influenza disease or immunization by assessing newborns. In the Mother's Gift study, we noted that the effectiveness of antenatal immunization in clinical episodes and influenza test positivity was observed mostly in the latter part of the study.4Zaman K. Roy E. Arifeen S.E. et al.Effectiveness of maternal influenza immunization in mothers and infants.N Engl J Med. 2008; 359: 1555-1564Crossref PubMed Scopus (971) Google Scholar Influenza rapid test data from our study as well as independent influenza surveillance data in Dhaka, Bangladesh,10Brooks W.A. Goswami D. Rahman M. et al.Influenza is a major contributor to childhood pneumonia in a tropical developing country.Pediatr Infect Dis J. 2010; 29: 216-221Crossref PubMed Scopus (105) Google Scholar showed that influenza was not circulating from October through January and had substantial circulation after January 31, 2005. We summarize a recent analysis of newborn outcomes related to the seasonality of influenza virus circulation and the similar seasonality of influenza vaccine effect on illness. A statistical test of interaction between the vaccine group and the low/high influenza circulation intervals was statistically significant (P = .016). We evaluated the outcomes of the subset of 116 infants born in the February-June 2005 period because they were in utero for 1-4 months while influenza virus circulated in Dhaka, during the period of clinically effective influenza vaccine protection. This post hoc subgroup analysis is justified by the strong biological paradigm of assessing the effect of a vaccine while the vaccine-specific pathogen is known to be present in the community. FIGURE 1, FIGURE 2 show that there was little difference in mean birthweights before Jan. 31 but a difference of 200 g in the mean weights after that date. Similarly, the proportion of infants who were small for gestational age was reduced by 57% (95% CI, 6–80%) during the same period.11Steinhoff M.C. Omer S.B. Roy E. et al.Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial.CMAJ. 2012; 184: 645-653Crossref PubMed Scopus (162) Google Scholar Our estimate from this study of the number needed to vaccinate to prevent 1 small-for-gestational-age neonate is 6-10 pregnant women.11Steinhoff M.C. Omer S.B. Roy E. et al.Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial.CMAJ. 2012; 184: 645-653Crossref PubMed Scopus (162) Google ScholarFIGURE 2Mean birthweight by study interval, by vaccine11Steinhoff M.C. Omer S.B. Roy E. et al.Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial.CMAJ. 2012; 184: 645-653Crossref PubMed Scopus (162) Google ScholarShow full captionFlu, influenza; PPS23V, pneumococcal polysaccharide 23 valent vaccine.aMean difference = 30 g (95% confidence interval, −98 to 157 g); bMean difference = 200 g (95% confidence interval, 191–209 g).Steinhoff. Antenatal influenza Immunization. Am J Obstet Gynecol 2012.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Flu, influenza; PPS23V, pneumococcal polysaccharide 23 valent vaccine. aMean difference = 30 g (95% confidence interval, −98 to 157 g); bMean difference = 200 g (95% confidence interval, 191–209 g). Steinhoff. Antenatal influenza Immunization. Am J Obstet Gynecol 2012. In a retrospective cohort study using surveillance data from Georgia, we evaluated the association between the receipt of influenza immunization in pregnancy and the likelihood of preterm births and small-for-gestational-age births.12Omer S.B. Goodman D. Steinhoff M.C. et al.Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study.PLoS Med. 2011; 8: e1000441Crossref PubMed Scopus (203) Google Scholar In this study, preterm birth was defined as birth before 37 weeks of gestation. The analysis was stratified by the intensity of the influenza activity in the study area: the full study period, putative influenza season, period of at least local influenza activity, period of at least regional activity, and the period of widespread influenza activity. The preinfluenza period was the comparison period. There was no statistically significant association between maternal influenza immunization and either preterm birth or small-for-gestational-age birth during the full study period (which included the summer months). However, during the putative influenza season, there was 40% reduction in the odds of preterm birth (adjusted odds ratio [OR], 0.60; 95% CI, 0.38–0.94). The association of influenza immunization in pregnancy and preterm birth increased with the increase in the intensity of influenza circulation, with the highest impact in the period of widespread influenza circulation (adjusted OR, 0.28; 95% CI, 0.11–0.74). The association between maternal influenza immunization and prevention of small-for-gestational-age birth was significant only for the period of widespread influenza activity (adjusted OR, 0.31; 95% CI, 0.13–0.75). Neonates born to vaccinated women had 96.7 g higher birthweight compared with neonates of unvaccinated women (3348 vs 3251 g; P = .002). During the putative influenza season, the difference between the mean birthweight in the 2 groups increased to 113 g (3360 vs 3247 g; P = .004). The difference in birthweights was not statistically significant outside the putative influenza season. The association of vaccine effect with the presence of influenza in the community is an important characteristic of these observations. The preventive fraction for preterm birth ranged from 7.93% in the putative influenza season to 17.52% in the period of widespread influenza activity (Figure 3).12Omer S.B. Goodman D. Steinhoff M.C. et al.Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study.PLoS Med. 2011; 8: e1000441Crossref PubMed Scopus (203) Google Scholar A recent report from Canada analyzed A/H1N1 pdm09 adjuvanted vaccine administered to 23,340 pregnant women, compared with 32,230 who were not immunized.13Fell D.B. Sprague A.E. Liu N. Yasseen A.S. Wen S.W. Smith G. Walker M.C. Better Outcomes Registry & Network (BORN) OntarioH1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes.Am J Public Health. 2012; 102: e33-e40Crossref PubMed Scopus (106) Google Scholar The immunized mothers were less likely than unimmunized mothers to have an SGA infant (risk ratio, 0.90; 95% CI, 0.85–0.96), preterm birth (<32 weeks; risk ratio, 0.73; 95% CI, 0.53–0.91), or fetal death (risk ratio, 0.66; 95% CI, 0.47–0.91). In a 13-year retrospective Canadian cohort study, McNeil et al14McNeil S.A. Dodds L.A. Fell D.B. et al.Effect of respiratory hospitalization during pregnancy on infant outcomes.Am J Obstet Gynecol. 2011; 204: S54-S57Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar evaluated the potential association between maternal hospitalization for respiratory conditions during the influenza season and the risk of neonatal morbidity. The study cohort included all singleton births in Nova Scotia, Canada, between 1990 and 2002. In this study, respiratory illness–related hospitalizations of pregnant women during the influenza season were associated with an increased risk of small-for-gestational-age births (adjusted relative risk [RR], 1.66; 95% CI, 1.11–2.49). Moreover, the mean birthweight of infants born to hospitalized women was 86.7 g lower than the mean birthweight of infants born to women without respiratory illness–related hospitalization during the influenza season. There was no significant difference between the 2 groups in the relative risk of preterm births (adjusted RR, 1.20; 95% CI, 0.71–2.04) (Table 1 and FIGURE 4, FIGURE 5).FIGURE 5Odds ratios for proportion SGA births to immunized vs unimmunized and unexposed vs exposedShow full captionCI, confidence interval; SGA, small-for-gestational-age.Steinhoff. Antenatal influenza Immunization. Am J Obstet Gynecol 2012.View Large Image Figure ViewerDownload Hi-res image Download (PPT) CI, confidence interval; SGA, small-for-gestational-age. Steinhoff. Antenatal influenza Immunization. Am J Obstet Gynecol 2012. Pierce et al15Pierce M. Kurinczuk J.J. Spark P. Brocklehurst P. Knight M. Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study.BMJ. 2011; 342 (Accessed Feb. 23, 2012): d3214http://www.bmj.com/content/342/bmj.d?tab=responsesCrossref PubMed Scopus (205) Google Scholar conducted a study to compare the birth outcomes between women who were hospitalized with 2009/H1N1 infection during the 2009/2010 H1N1 influenza pandemic with a comparison cohort of women who delivered between February 2005 and February 2006. Eligible women in this national level cohort study were enrolled through the UK Obstetric Surveillance System network of collaborating clinicians. Infants of hospitalized women with H1N1 infection were 4 times more likely to be preterm (adjusted RR, 4.0; 95% CI, 2.7–5.9) compared with infants of women in the nonconcurrent comparison cohort. Women in the infected cohort with a preterm birth had a higher likelihood of being infected in the third trimester (P = .046), being admitted to an intensive care unit (P < .001), and to have had a secondary pneumonia (P = .001), compared with women in the same cohort who had a term delivery. In subsequent analyses, the proportion of small-for-gestational-age births in the infected cohort was11% compared with 7% (n = 90) in the comparison cohort (P = .051; OR, 1.56; 95% CI, 0.96–2.47) (Table 2 and Figure 4).TABLE 2Antenatal influenza immunization and fetal/newborn outcomesAuthor (reference)Site/yearsDesignNumber of subjectsNewborn outcomeaExpressed as efficacy (percent reduction of infant outcome).InterventionControlBirthweight difference, gSGA reduction (95% CI)Steinhoff et al, 201211Steinhoff M.C. Omer S.B. Roy E. et al.Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial.CMAJ. 2012; 184: 645-653Crossref PubMed Scopus (162) Google ScholarBangladesh, 2004–2005Randomized controlled trial (secondary analysis)Influenza vaccine: 58Pneumococcal vaccine: 5820057% (6–80%)Omer et al, 201112Omer S.B. Goodman D. Steinhoff M.C. et al.Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study.PLoS Med. 2011; 8: e1000441Crossref PubMed Scopus (203) Google ScholarGeorgia, 2004–2006Cohort analysisInfluenza vaccine: 578No vaccine: 374811870% (25–87%)McNeill et al, 201114McNeil S.A. Dodds L.A. Fell D.B. et al.Effect of respiratory hospitalization during pregnancy on infant outcomes.Am J Obstet Gynecol. 2011; 204: S54-S57Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarNova Scotia, Canada, 1990–2002RetrospectiveFlu season hospital admissions: 208Not hospitalized: 132,0999040% (10–60%)Mendez-Figueroa et al, 201116Mendez-Figueroa H. Raker C. Anderson B.L. Neonatal characteristics and outcomes of pregnancies complicated by influenza infection during the 2009 pandemic.Am J Obstet Gynecol. 2011; 204: S58-S63Abstract Full Text Full Text PDF PubMed Scopus (51) Google ScholarRhode Island, 2009–2010Prospective cohort (pH1N1)Laboratory-positive influenza: 16ILI, laboratory negative: 25285—Pierce et al, 201115Pierce M. Kurinczuk J.J. Spark P. Brocklehurst P. Knight M. Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study.BMJ. 2011; 342 (Accessed Feb. 23, 2012): d3214http://www.bmj.com/content/342/bmj.d?tab=responsesCrossref PubMed Scopus (205) Google ScholarUnited Kingdom, 2009–2010RetrospectiveLaboratory-positive influenza: 256Deliveries, 2005–2006: 1220255—CI, confidence interval; ILI, influenza-like illness; SGA, small-for-gestational-age.Steinhoff. Antenatal influenza Immunization. Am J Obstet Gynecol 2012.a Expressed as efficacy (percent reduction of infant outcome). Open table in a new tab CI, confidence interval; ILI, influenza-like illness; SGA, small-for-gestational-age. Steinhoff. Antenatal influenza Immunization. Am J Obstet Gynecol 2012. There were more perinatal infant deaths in the infected cohort (39 per 1000 births; 95% CI, 19–71) vs the comparison cohort (7 per 1000 births; 95% CI, 3–13; P < .001). This disparity in perinatal mortality was almost exclusively due to the higher rate of stillbirth among the infected cohort compared with the comparison cohort (27 per 1000 births vs 6 per 1000 total births; P = .001).15Pierce M. Kurinczuk J.J. Spark P. Brocklehurst P. Knight M. Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study.BMJ. 2011; 342 (Accessed Feb. 23, 2012): d3214http://www.bmj.com/content/342/bmj.d?tab=responsesCrossref PubMed Scopus (205) Google Scholar Mendez-Figueroa et al16Mendez-Figueroa H. Raker C. Anderson B.L. Neonatal characteristics and outcomes of pregnancies complicated by influenza infection during the 2009 pandemic.Am J Obstet Gynecol. 2011; 204: S58-S63Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar enrolled 45 pregnant women in Rhode Island with ILI between June 2009 and March 2010 in a prospective cohort study. In this relatively small study, birth outcomes were available for 41 mother-infant pairs. Of these, 16 had evidence of 2009 H1N1 infection. Compared with women with non–2009 H1N1-related ILI, the 2009 H1N1–infected women had infants with lower mean birthweights (3186 vs 3471 g; P = .04). All other birth outcomes, such as Apgar score, cord pH, and gestational age at birth, were similar between the 2 groups (Table 2 and FIGURE 4, FIGURE 5). These observations in multiple sites suggest that influenza infection during pregnancy can affect intrauterine growth and perhaps can trigger preterm labor. Reduced birthweights are a signal that intrauterine growth was not optimal. The intrauterine growth effects we have described are not trivial. The long-term effects of full-term, small-for-gestational-age status include decreased adult height, reduced academic performance, decreased IQ at age 18 years, and increased prevalence of adult chronic disease, including obesity, coronary heart disease, diabetes, and stroke.17Lundgren E.M. Tuvemo T. Effects of being born small for gestational age on long-term intellectual performance.Best Pract Res Clin Endocrinol Metab. 2008; 22: 477-488Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 18Gluckman P.D. Hanson M.A. Cooper C. Thornburg K.L. Effect of in utero and early-life conditions on adult health and disease.N Engl J Med. 2008; 359: 61-73Crossref PubMed Scopus (2581) Google Scholar We are embarked on a new randomized controlled trial to assess the validity of these observations in a field site in Nepal. These new findings do have a biological coherence with other observations. Pandemic influenza in pregnant women is associated with miscarriage, preterm birth, and reduced birthweight.1Mak T.K. Mangtani P. Leese J. Watson J.M. Pfeifer D. Influenza vaccination in pregnancy: current evidence and selected national policies.Lancet Infect Dis. 2008; 8: 44-52Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 19Siston A.M. Rasmussen S.A. Honein M.A. et al.Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States.JAMA. 2010; 303: 1517-1525Crossref PubMed Scopus (715) Google Scholar Reviews of the seasonality of preterm birth in high-latitude regions show an increase of preterm birth in late winter and spring.20Strand L.B. Barnett A.G. Tong S. The influence of season and ambient temperature on birth outcomes: a review of the epidemiological literature.Environ Res. 2011; 111: 451-462Crossref PubMed Scopus (184) Google Scholar An additional observation from Bangladesh is that although maternal serum antibody is transferred to the infant and declines with a half-life of about 35 days, we showed solid clinical protection out to 6 months of age when little passive maternal antibody is present.3Henkle E. Steinhoff M.C. Omer S.B. et al.Incidence of influenza virus infection in early infancy: a prospective study in South Asia.Pediatr Infect Dis J. 2011; 30: 170-173Crossref PubMed Scopus (18) Google Scholar We have preliminary data that maternal antenatal immunization results in increased breast milk–specific immunoglobulin A concentrations for as long as 1 year after delivery. In addition, antenatal immunization is reflected in a doubling of influenza virus neutralization titers in breast milk. It has been known that breastfeeding can reduce respiratory infections in infants, but our randomized controlled trial immunization study shows a specific increase in breast milk neutralization related to antenatal immunization.21Steinhoff MC, Schlaudecker EP, Omer SB, Roy E, Zaman K. Influenza IgA antibody in human milk: a randomized trial of maternal influenza immunization. Publication 3420A. 4. Presented at the annual meeting of the Pediatric Academic Society, Denver, CO, 2011.Google Scholar Respiratory infections in pregnancy have been associated with preterm birth and reduced growth of the fetus.22Goldenberg R.L. Culhane J.F. Iams J.D. Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Abstract Full Text Full Text PDF PubMed Scopus (4619) Google Scholar The 2 possible mechanisms usually invoked regarding the effects of antenatal maternal infections on the fetus are the following: (1) vertical transmission or infection of the fetus through the placenta as seen in malaria, syphilis, or cytomegalovirus; or (2) ascending infection, fetal infection through the cervix caused by Chlamydia, Ureaplasm, and other genital organisms. Neither of these classical mechanisms appears to explain the fetal effect of influenza infection. Transplacental transmission of influenza is reported during pandemic periods but is relatively rare with seasonal influenza.1Mak T.K. Mangtani P. Leese J. Watson J.M. Pfeifer D. Influenza vaccination in pregnancy: current evidence and selected national policies.Lancet Infect Dis. 2008; 8: 44-52Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar We are aware of only 5 reported occurrences of transplacental transmission of influenza virus.11Steinhoff M.C. Omer S.B. Roy E. et al.Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial.CMAJ. 2012; 184: 645-653Crossref PubMed Scopus (162) Google Scholar This observation suggests that the effect of seasonal influenza illness on intrauterine growth is likely an indirect effect of maternal infection with the resulting high levels of proinflammatory cytokines23Eccles R. Understanding the symptoms of the common cold and influenza.Lancet Infect Dis. 2005; 5: 718-725Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar and the maternal immune response acting on placental function and on the fetus. Further research on the mechanisms of this indirect effect of maternal influenza is needed to provide a basis for preventive and treatment interventions. In summary, studies by our group and others show that antenatal influenza disease affects the mother and the fetus and that influenza vaccine can prevent disease and its consequences in the mother, her fetus, and the infant to 6 months of age. Confirmation and replication of these findings are needed and is being undertaken by Bill and Melinda Gates Foundation–funded projects in Nepal, Mali, and South Africa.24Adegbola R. Nesin M. Wairagkar N. 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