Over seven influenza seasons, 2122 hospitalized infants were eligible for enrollment in the three NVSN sites and 1423 (67%) of the eligible infants were included from the inpatient setting (). Reasons for exclusion were 307 (44%) protocol deviation at Cincinnati, 132 (19%) parental refusal, 130 (19%) parents missed or not available, 89 (13%) lack of language translator, 38 (5%) discharged prior to being approached, and 3 (<1%) physician refusal. Of these 1423 hospitalized and enrolled infants, 57 (4%) had unknown or missing maternal influenza vaccination status, 3 (0.2%) had indeterminate influenza status (i.e., negative RNA control), 3 (0.2%) had unknown race/ethnicity, and 23 (2%) represented a second study hospitalization during the influenza season and were excluded from analysis. The overall study population comprised these 1337 eligible infants enrolled solely from the inpatient setting and an additional 173 eligible infants who were hospitalized following enrollment in the emergency department and fulfilled all inpatient enrollment criteria. Among these 1510 infants hospitalized with fever and/or respiratory symptoms during the influenza season (), 151 (10%) had laboratory-confirmed influenza —with 136 (90%) influenza A and 15 (10%) influenza B. Among all hospitalized infants, a higher proportion of infants <2 months than those 2–<6 months of age were influenza-positive. The proportion of infants who were influenza-positive varied significantly across study years, ranging from 3% in 2006–2007 to 15% in 2003–2004.
Characteristics of infants <6 months of age hospitalized with and without laboratory-confirmed influenza.
A total of 294 (19%) mothers reported that they had received the influenza vaccine during that pregnancy (). This proportion varied by influenza season, ranging from 10% in 2003–2004 to 38% in 2008–2009, and by age of the infant at the time of enrollment during the influenza season, ranging from 24% for neonates younger than 1 month to 9% for infants 4–5 months of age. The proportion of infants whose mothers were vaccinated varied from only 13–15% at the Cincinnati and Nashville sites up to 33% at the Rochester site. The proportion of infants whose mothers were vaccinated was 15% for blacks, 21% for whites, and 22% for Hispanics, respectively. Infants with private insurance were more likely to have a vaccinated mother than those with public or no insurance. Breastfed infants were more likely to have mothers who reported being vaccinated than infants of mothers who never breastfed. Non-smoking households had a higher proportion of infants whose mothers were vaccinated than households with a smoker.
Characteristics of hospitalized infants < 6 months of age by maternal influenza vaccination status.
Among influenza-positive infants during all study years, 12% of their mothers reported influenza vaccination during pregnancy, while among influenza-negative infants, 20% of their mothers reported influenza vaccination, yielding an unadjusted odds ratio of 0.53 (95% confidence interval, CI, 0.32–0.88). Similar results were obtained in the three multivariate models shown in . Since a significant proportion of data from Cincinnati was excluded for protocol violations, a sensitivity analysis that included only Rochester and Nashville data was performed and yielded similar results to the combined data. In the core demographic model, adjusting for age, gender, race/ethnicity, site, study year, and early, middle or late influenza season, the odds ratio for having an influenza-positive, hospitalized infant among vaccinated mothers was 0.55 (95% CI 0.32–0.95). Model 2 included the core demographic model plus prematurity and high-risk conditions and had an odds ratio of 0.55 (95%CI 0.32–0.94). These medical covariates did not impact the estimate and were not included in the third model. Model 3 included the core demographic model, exposure to smoke, siblings, daycare, insurance and presence of breastfeeding and had an odds ratio of 0.52 (95% CI 0.30–0.91). As shown, adjustments for covariates did not affect the results substantially. Overall, results of the multivariate modeling suggest that maternal vaccination reduced the risk of influenza by 45%–48%.
The odds ratio and 95% confidence interval for the protection provided by influenza vaccination during pregnancy on laboratory-confirmed influenza hospitalizations among infants for unadjusted and adjusted models.
A total of 110 mothers from 2005–2006 through 2008–2009 reported a history of influenza-like illness during pregnancy, of which 81 (74%) had not received the influenza vaccine during that pregnancy. In a sub-analysis combining both maternal influenza vaccination for all seven years and a history of an influenza-like illness during pregnancy for four years, we found that the unadjusted and adjusted estimates were similar with a 45%–49% reduced risk of influenza in the infant.
Our results indicate that hospitalized infants whose mothers received influenza vaccine during pregnancy were 45% to 48% less likely to have laboratory-confirmed influenza during their first influenza season compared with infants of unvaccinated mothers. Adding history of influenza-like illness during pregnancy to the analyses had little impact on the odds ratio for having an influenza-positive, hospitalized infant. Given that infants <6 months of age have the highest hospitalization rate among all children2–6
and that the vaccine is not licensed for that age group,16
these data support that infants born to vaccinated mothers benefit from the transfer of maternally derived antibodies.
Four previously published studies support our conclusions. First, a prospective, observational study among Native Americans from 2002–2005 found that infants of vaccinated mothers had a 41% reduction of the risk of laboratory-confirmed influenza infection in the inpatient and outpatient settings as determined by viral culture or antibody titers (relative risk 0.59, 95% CI 0.37–0.93).20
A second study, a randomized controlled trial of maternal influenza vaccination during pregnancy, was conducted in Bangladesh in 2004–2005. In this tropical country with year-round influenza circulation, investigators reported fewer rapid test-confirmed influenza cases among infants of mothers who received influenza vaccine compared with infants of unvaccinated mothers (6 infants versus 16 infants, respectively) for a vaccine effectiveness estimate of 63% (95% CI 5%–85%). Among 110 infants in the influenza vaccine group and 153 infants in the control group, vaccine effectiveness against unspecified respiratory illness with fever was 29% (95% CI 7%–46%).19
Third, a matched case-control study compared hospitalized infants with physician-ordered direct fluorescent antibody for seasonal influenza from 2000 through 2009. Cases with a positive influenza test and controls with a negative test were matched by date of birth and date of hospitalization. Maternal vaccinations were included only if they were confirmed and given at least 14 days prior to delivery. Effectiveness of maternal vaccination among infants <6 months of age was reported to be 91.5% (95% CI 62%–98%).30
Fourth, a Northern California Kaiser Permanente database study over 5 influenza seasons (1997–2002), found that maternal vaccination was associated with a decreased risk of pneumonia or influenza hospitalization in their infants with an adjusted hazard ratio of 0.63 (95%CI 0.30–1.29), translating into 37% protection.31
Our 95% confidence intervals for protection of maternal vaccination from influenza hospitalizations among infants <6 months of age overlap those from each of these studies.
Our study differs from the previously published studies in several ways. First, we included seven consecutive influenza seasons and used prospective, population-based and laboratory-confirmed surveillance to identify eligible infants. By systematically testing all eligible infants using culture and molecular methods to define influenza infections, we utilized sensitive and specific methods and avoided the biases associated with physician-ordered testing; the study utilizing physician-ordered testing to identify eligible infants had a much higher proportion of infants with high-risk conditions than our study population. Second, we focused on hospitalizations whereas two previous studies included more outpatient visits than hospitalizations. Third, we included three diverse geographic regions of the U.S whereas all previous studies reported data from one geographic region.
Our study has several limitations. Although we enrolled a large proportion of eligible infants a number of them had to be excluded because of protocol violations, and infants who were and were not included in the study population could have systematically differed. Neither confirmed influenza vaccination status nor documented influenza disease status was available from mothers, and serologic assays were not performed on either infants or mothers. Since the study focused on hospitalized infants and not those seen only in the outpatient clinic or emergency departments, the generalizability of these results to outpatient settings is unknown. However, admission criteria for infants with fever and respiratory symptoms change over the first few weeks of life, so limiting the study population to solely inpatients allowed us to focus on severe outcomes.
Our estimates of maternal vaccination are consistent with national estimates,17
and lower than estimates from one health care system that implemented interventions to increase their maternal vaccination rates.33
We have previously reported higher influenza vaccine coverage among children 6–59 months of age in Rochester than that in Nashville or Cincinnati.34
Because of this consistent pattern, these differences seem to reflect geographical differences in influenza vaccination patterns. We found higher rates of maternal vaccination when the infant had private insurance compared with public or no insurance. This differs from the seasonal influenza vaccine coverage reported the Rhode Island Pregnancy Risk Assessment Monitoring System (PRAMS), which found similar coverage between women with public and private insurance. Given that obstetrician-gynecologists have consistently identified financial costs as a major barrier to influenza vaccination of pregnant women,35–37
it is possible that differences in vaccine coverage between public and private insurance vary geographically.
Maternal vaccination during pregnancy is recommended since pregnant women have an increased risk of influenza-associated morbidity and mortality.11–15
However, despite this recommendation, pregnant women have traditionally had the lowest influenza vaccine coverage of any group for whom influenza vaccine is specifically recommended.17
Although most (84.5%) obstetricians support influenza vaccination of all pregnant women,35
few mothers (20%) actually report being offered influenza vaccination during pregnancy.38
Obstetricians play a critical role in the influenza vaccination coverage of pregnant women. For first pregnancies, obstetricians are often the only medical professional seeing the pregnant women; for subsequent pregnancies, pregnant women may see the pediatrician, however pediatricians do not tend to vaccinate pregnant women since they are not their patients. Half of all pregnant women who received the monovalent H1N1 vaccine in 2009–2010 reported receiving it in the obstetrician/gynecologist office and none reported receiving it in a pediatric office.18
Because numerous studies have demonstrated comparable or increased influenza antibody titers in the cord blood when compared with maternal levels,3,39–44
maternal vaccination should afford some protection of newborn infants against influenza and is supported by our study. Similar to other studies, we found between 45% and 48% protection against laboratory-confirmed influenza hospitalizations among infants whose mothers reported receiving influenza vaccine during pregnancy. Using data from our earlier studies of 4.5 influenza-attributable hospitalizations among 1000 infants <6 months of age2
and census data of 4,251,095 live-births in the U.S. in 2008,45
we project that there are an average of 19,130 influenza-attributable hospitalizations among infants <6 months of age per year. A 45% to 48% reduction in this burden would yield an estimated 8600 to 9200 fewer influenza-attributable hospitalizations among young infants each year. Thus, our findings suggest that influenza vaccination of pregnant women may reduce the risk of influenza-attributable hospitalization among infants in the first 5 months of life, further supporting the current influenza vaccination recommendations for pregnant women.