Invasive pneumococcal disease (IPD) is a major cause of morbidity and mortality in children less than 2 years of age.1 Knowledge about risk factors for IPD is important to implement the best immunization strategy.
In Norway, 7-valent conjugated pneumococcal vaccine (PCV7) was included in the childhood immunization program in July 2006, with a catch-up campaign for children born in 2006. A 2 + 1 schedule, with vaccination at 3, 5 and 12 months was recommended, irrespective of gestational age (GA). The vaccination coverage among 2-year olds was 86% for children born in 2006 and 92% for children born in 2009. In Norway, the vaccine program effectiveness (all serotypes) was estimated shortly after vaccine introduction to 74% in children less than 2 years of age.2 PCV7 reduced the incidence rate of IPD in children less than 2 years of age and also in other age groups not targeted by vaccination, indicating indirect protection similar to other countries.3,4
Worldwide, more than 1 in 10 babies are born preterm, that is, before 37 completed weeks of gestation.5 A few previous studies reported increased risk of IPD in children born preterm or with low birth weight.6,7 In a Danish case–control study, the increased risk among preterm children was particularly high during the first 6 months, especially if they had older siblings.7 An immature immune system, incomplete transfer of maternal antibodies,8 comorbidities and immunosuppressive drugs such as corticosteriods9 are partial explanations for the increase in risk of IPD for preterm children.
To our knowledge, the risk of IPD among preterm children has not been investigated in a cohort study. Furthermore, the impact of widespread immunization with PCV on IPD incidence rates in preterm children is unknown.
We used high-quality Norwegian registry data to determine whether there was a higher risk of IPD among preterm, compared with full-term children, during the first 2 years of life. We also studied whether the introduction of PCV7 in the childhood vaccination program reduced the incidence rate of IPD for preterm and full-term children.
MATERIALS AND METHODS
We identified all live births in Norway between January 1, 2000, and December 31, 2010, through the Norwegian Medical Birth Registry (MBRN). The MBRN contains extensive information about the pregnancy, delivery and the infant. GA is based on ultrasonography or the mother’s last menstrual period if ultrasonography is not recorded. The MBRN also contains date of death or date of emigration (obtained through linkages with the Central Population Register on a regular basis). All Norwegian residents are assigned a unique, 11-digit identification number providing a link of the MBRN data with the Norwegian Surveillance System for Communicable Diseases (MSIS) and the Norwegian Immunisation Registry (SYSVAK). Each parent’s country of birth and level of education were obtained from Statistic Norway. Ethical clearance was obtained from the Regional Committee for Medical and Health Research Ethics, Southeast Norway.
An IPD case was defined as a case in which Streptococcus pneumoniae was isolated from a normally sterile body site, including positive culture from blood or cerebrospinal fluid, or detection of S. pneumoniae in cerebrospinal fluid by antigen test or nucleic acid amplification. Notification of IPD cases to MSIS by laboratories and clinicians is mandatory. S. pneumoniae isolates from IPD cases were forwarded to the National Reference Laboratory for pneumococci and serotyped by the Quellung reaction using serotype-specific antisera (Statens Seruminstitut, Copenhagen, Denmark). The serotypes included in PCV7 (4, 6B, 9V, 14, 18C, 19F and 23F) were classified as vaccine serotypes for this study.
Since 1995, all vaccinations received within the Norwegian childhood vaccination program are recorded in SYSVAK.10 In 2011, after the end follow-up for this study, PCV7 was replaced by PCV13 in the Norwegian program.
Based on GA, the infants were categorized as full-term (≥37 weeks) or preterm (23 weeks to 36 weeks 6 days). Preterm infants were further categorized as 23–31 weeks 6 days and 32–36 weeks 6 days.
Each child’s number of siblings at birth was defined as the number of previous births to the mother and categorized as 0, 1, 2 or ≥ 3. Children were classified as having an immigrant background if at least 1 parent was born outside Norway. Parental education was defined as mother’s attained education, categorized as compulsory education, secondary education, undergraduate level higher education or graduate level higher education. Father’s attained education was used for the 13,221 (2.2%) children where we did not have information on the mothers’ education.
Study Population and Follow-up
All children born alive in the period 2000–2010 who were residents of Norway were eligible for the study (n = 644,595). Follow-up started at date of birth for children born in 2002 and later, or on January 1, 2002, for children born before 2002. The children were followed until first diagnosis of IPD, death, emigration, the day before their second birthday, or December 31, 2010, whichever occurred first. We excluded 1113 children who died, emigrated, turned 2 years or were diagnosed with IPD before January 1, 2002, because these children did not contribute full follow-up time to the study period. We also excluded children who died within the first week of birth (n = 830), children with a reported GA <23 weeks 0 days (n = 33) or ≥45 weeks 0 days (n = 149), unknown GA (n = 4898) or unknown birth weight (n = 374). Children with birthweight outside 3 standard deviation of sex- and GA-specific mean (n = 3738) were also excluded because we assumed that the recorded GA was incorrect.11,12 Finally, we excluded 320 children with missing information on both parents’ country of birth, and 5002 children with missing information on both parents’ level of education. A total of 628,138 children were included in the main analyses.
We defined 2 additional study periods: the pre PCV7-period (2002–2005) and the PCV7-period (2007–2010). In the pre PCV7-period, the children were followed until December 31, 2005. In the PCV7-period, follow-up started January 1, 2007. Follow-up time from 2006, the year of PCV7 introduction, was not included in either of these 2 periods. Also, because children born in 2005 were not offered PCV7, they were excluded from analyses of the PCV7-period. Furthermore, we defined 2 separate age categories: 0–5 months defined as 0–182 days and 6–23 months defined as 183–730 days. We used chronologic age.
We used the Fisher mid-p test13 to compare the proportion of preterm and full-term IPD cases that were hospitalized, were <6 months of age, had meningitis or were caused by vaccine serotype. Mean age at diagnosis was compared with a t test. We calculated crude incidence rates (number of events divided by accrued follow-up time) of reported IPD in preterm and full-term children. Rates were calculated for the entire study period, the pre-PCV7-period and the PCV7-period. Further, in each period, we calculated rates for children 0–23, 0–5 and 6–23 months of age. We used chrono logic age. Incidence rate ratios (IRRs) and corresponding 95% confidence intervals (CIs) were estimated with Poisson regression. The multivariate model was adjusted for attained age (time scale; 0–182, 183–273, 274–364, 365–546 and 547–730 days), sex of child, parental education, immigrant background, number of siblings and number of doses of PCV7 (0, 1, 2 or 3) because we considered these to be potential confounders. The number of received PCV7 doses was updated 14 days after each dose. When the analyses were limited to children 0–5 months of age, vaccination was still a time-dependent variable with a lag of 14 days, but with only 2 categories (0 doses or ≥1 dose) because only a small proportion of follow-up time (2.1%) in this age group was categorized as 2 or 3 doses. We did not adjust for PCV7 vaccination in the pre-PCV7 period. When we compared rates in the pre-PCV7-period and the PCV7-period, follow-up time from both periods was included in the analysis and an indicator of period was added to the model. The comparisons were done separately for preterm and full-term children. We did not adjust for PCV7 vaccination in these analyses because the objective was to assess whether the incidence rates had decreased, not to evaluate vaccine effectiveness. To further explore the association between GA and risk of IPD, we did additional analyses with GA as a continuous variable. All tests were 2 sided, and P < 0.05 was considered statistically significant. The data were analyzed with Stata/SE 14.0 (StataCorp, College Station, TX).
Of the 628,138 children included in our study, 41,931 (6.7 %) were born preterm. Characteristics of children in the study by GA are shown in Table 1.
All 411 IPD cases were laboratory confirmed, 323 (78.6%) from blood, 46 (11.2 %) from spinal fluid, 37 (9.0 %) from blood and spinal fluid and 5 (1.2 %) from other material. Two children had more than 1 episode of IPD, but only the first episode was included in the analyses.
There were 244 cases in the pre-PCV7-period (2002–2005) and 82 cases in the PCV7-period (2007–2010). Age at diagnosis was significantly higher in the pre-PCV7-period than in the PCV7-period (385 days vs. 316 days; P = 0.002). Furthermore, 85 cases were not included in the comparison of periods (cases from year of PCV7 introduction in 2006 or cases from the PCV7-period in children born in 2005). In 50 (12.2%) IPD cases, the children were preterm. Among preterm cases, 42 (84%) had GA 32–36 weeks, 5 (10%) had GA 31–28 and 3 (6%) had GA 23–27 weeks. During the PCV7 period, the proportion of cases 0–5 months of age was higher among preterm than in full-term cases, 54.5% versus 23.9%, P value = 0.047 (Table 2). The distribution of IPD serotypes among all cases in the PCV7 period is shown in Figure 1.
In the entire study period, the risk of IPD was significantly increased for preterm children compared with full-term children for the age intervals 0–23, 0–5 and 6–23 months, IRRs = 1.83 (95% CI: 1.36–2.47), 2.95 (95% CI: 1.44–6.06) and 1.69 (95% CI: 1.22–2.34), respectively (Table 3). During the pre-PCV7-period, a statistically significant increased risk was observed for preterm children 0–23 and 6–23 months of age, IRRs = 1.68 (95% CI: 1.13–2.49) and 1.66 (95% CI: 1.09–2.51), respectively. During the PCV7-period, an increased risk for IPD for preterm children was observed for those 0–23 and 0–5 months of age, IRR = 2.18 (95% CI: 1.15–4.13) and 5.71 (95% CI: 2.25–14.5). The IRRs comparing preterm to full-term children are displayed graphically in Figure 2.
Compared with full-term children, we observed significantly higher rates in the entire study period both for children with GA 32–36 weeks and with GA 23–31 weeks, IRR = 1.79 (95% CI: 1.30–2.47) and 2.10 (95% CI: 1.04–4.24), respectively, for 0–23 months of age. The risk of IPD decreased with increasing GA (Table, Supplemental Digital Content 1, http://links.lww.com/INF/D56). In the entire study period, IRR per week increase in GA was 0.91 (95% CI: 0.88–0.95) for children 0–23 months of age. The association between GA and risk of IPD was similar across the study periods and age groups. However, the association was not significant for children 6–23 months of age in the PCV7 period.
In full-term children, a significant decrease in the rate of IPD from the pre-PCV7-period to the PCV7-period was observed for children 0–23 and 6–23 months of age, IRRs = 0.33 (95% CI: 0.25–0.43) and 0.28 (95% CI: 0.21–0.38) (Table 4). In preterm children, we also observed a statistically significant decrease for children 0–23 and 6–23 months of age, IRRs = 0.40 (95% CI: 0.20–0.80) and 0.20 (95% CI: 0.08–0.53), respectively. However, the rate did not decrease among preterm children 0–5 months of age, IRR = 1.94 (95% CI: 0.48–7.8).
Restricting the analyses to only include singletons gave similar results; for the entire study period, IRRs for preterm compared with full-term children were 1.81 (95% CI: 1.29–2.54) for children 0–23 months of age, 2.97 (95% CI: 1.34–6.61) for children 0–5 months of age and 1.66 (95% CI: 1.14–2.41) for children 6–23 months of age.
In this registry-based study, preterm children had an increased risk of IPD compared with full-term children both before and after the introduction of conjugate pneumococcal vaccine in the general program. The increased risk that we observed remained statistically significant after adjustment for several socioeconomic factors, number of siblings, and vaccination status. The difference in risk was particularly evident for children 0–5 months of age. In both preterm and full-term children, the overall risk of IPD was reduced in the PCV7-period compared with the pre-PCV7-period for those who were ≥6 months of age, but a reduction was not evident for those 0–5 months of age.
The 1.8-fold increased IPD risk for all serotypes among preterm compared with full-term children 0–2 years of age that we observed was similar to that found for vaccine serotypes in a pivotal PCV7 efficacy trial.6
Preterm children 0–5 months of age had an almost 3-fold increased risk compared with full-term children. Similar data were reported in a Danish case–control study.7 In somewhat older preterm children, 6–23 months of age, the risk was increased almost 1.7-fold. This finding is also in correspondence with Danish data.7 This could be related to lower amounts of maternal antibodies transferred. Although PCV7 showed robust immunogenicity in preterm children, a study found that postvaccination geometric mean concentrations for 5 of the 7 PCV7 serotypes were lower in preterm children compared with full-term children.14 We observed a general reduction in IPD incidence rate among both preterm and full-term children 0–2 years of age after introduction of PCV7 in 2006. The reduction in IPD among full-term children in that age group is well documented in other studies2,15 and explained both by direct and indirect effects of mass vaccination programs.
We found that preterm children with low GA had a higher risk of IPD than those with higher GA. Nevertheless, we found a small difference in risk among those with GA 32–36 and 23–31 weeks.
This is somewhat in contrast with a Norwegian study on the risk of pertussis where the risk was higher among very preterm children compared with preterm children born close to term.16 One possible explanation for this difference is that waning of maternal antibodies by age may have less impact on risk of IPD, as 80% of IPD cases were ≥6 months of age. In the Norwegian pertussis study, cases mainly occurred in those less than 6 months of age.16 Nevertheless our data indicate that preterm children overall have increased risk compared with full-term children, and strategies to reduce the burden of IPD should therefore not only include those with GA less than 32 weeks.
The introduction of PCV7 in the childhood immunization program in Norway did not seem to have an indirect effect (herd immunity) for preterm and full-term children 0–5 months of age. Many of these IPD cases were too young to have been offered the first 2 doses in the Norwegian schedule at 3 and 5 months of age. This is in contrast to findings from a surveillance-based study for the United States.17 This could be because of a limited indirect effect on vaccine serotypes alone, or in combination with serotype replacement. Our numbers were too small to evaluate the possible effect on vaccine type versus nonvaccine type disease.
The lower age at diagnosis after introduction of PCV7 in Norway is as expected when an effective vaccine is introduced in a program with high vaccination coverage. The disease became rare among fully vaccinated children. Therefore, younger children who had not received their first doses represented a higher proportion of IPD cases.
A clear overall IPD reduction was found for preterm and full-term children 6–23 months of age. Other studies have shown declined incidence, both in age groups targeted for vaccination, for example, children 0–2 years of age,2 as well as in other age groups, for example, >65 years.3 Robust vaccine protection is obtained 14 days after the second dose2; hence, earlier vaccination may reduce the IPD disease burden further. At the same time, preterm infants may be more likely to have a lower vaccine response than full-term infants.18 A randomized controlled trial showed that the optimal schedule for preterm children will depend on when they are at most risk for IPD.19 Although all primary schedules, for example, 2 and 4 months; 2, 3 and 4 months; or 2, 4 and 6 months, showed adequate antibody response, the 2- and 4-month priming schedule resulted in higher postbooster concentrations but lower postprimary concentrations.19 Since 2013 (after the end of our follow-up period), Norwegian recommendations say that preterm infants <GA 32 weeks and/or <1500 g should be vaccinated starting with first dose at 2 months chronologic age; however, the schedule is not further specified.20 This epidemiologic study calls for revision of the current Norwegian recommendations for vaccination of preterm children.
One limitation of our study is that we had few cases among those with GA 23–31 weeks. This study also had limited number of cases with serotypes before PCV7 introduction so that a comparison of serotypes pre- and post-PCV7 introduction was not meaningful. In addition, we did not have information about other risk factors for IPD besides prematurity, such as coinfections or comorbidity. Preterm birth is associated with comorbidities; however, we believe that preterm birth is an important risk factor for IPD. Preterm birth has also been shown to increase the risk of other diseases such as pertussis, respiratory syncytial virus-associated hospitalizations and late-onset group B sepsis.16,21,22
The risk of IPD starts when a child is born both for full-term and preterm children. Preterm children are recommended to be vaccinated based on their chronologic age,23 partly because they are born with low levels of protective antibodies. PCV7 was shown to be effective for both full-term and for preterm children when vaccinated according to chronologic age.6 We therefore think that the epidemiologic data with respect to IPD should be based on chronologic age without correction.
It is possible that a 4-year follow-up was too short to observe indirect effects among children 0–5 months of age. Future studies should have a longer follow-up to measure public health impact. We should continue to collect and analyze robust data to assess direct and indirect effects of multivalent pneumococcal vaccines in different high-risk groups including preterm children.
Among the strengths of this study are the cohort design and large sample size that included all live births in Norway and linkage to other national registries of high quality. Reporting of IPD cases, vaccinations and birth data to national registries in Norway are mandatory and regulated by law. The sensitivity of our registry data is therefore assumed high.
In conclusion, we found preterm birth to be a risk factor for IPD in children 0–23 months of age, both before and after introduction of PCV7. In children 6–23 months of age, the risk for IPD in preterm and full-term children was reduced in the PCV7-period compared with the pre-PCV7-period but not for those 0–5 months of age. To reduce the incidence rate among preterm children less than 6 months of age, PCV vaccine could be administered with a first dose earlier than at 3 months chronologic age, and we suggest modification of the program.
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