PEDIATRICS Vol. 119 No. 4 April 2007, pp. e804-e812 (doi:10.1542/10.1542/peds.2006-2094)
ARTICLE |
Perinatal Risk Factors for Hospitalization for Pneumococcal Disease in Childhood: A Population-Based Cohort Study
a Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
b Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts
c Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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ABSTRACT |
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OBJECTIVE. The objective of this study was to examine the relation of factors that are present at birth to subsequent hospitalization for childhood pneumococcal disease.
METHODS. We conducted a cohort study of all singletons born in 3 counties in western Denmark from 1980 through 2001, using population-based registries to obtain data on pregnancy- and birth-related variables and hospitalizations through age 12. We calculated incidence rates of pneumococcal disease hospitalization overall and within strata of study variables and used Poisson regression to estimate rate ratios for pneumococcal disease hospitalization while accounting for other birth characteristics.
RESULTS. Among 338504 eligible births, 1052 children were later hospitalized for pneumococcal disease. Pneumonia accounted for most hospitalizations (81.9%). The pneumococcal disease hospitalization rate was highest among 7- to 24-month-olds, followed by 0- to 6-month-olds and 25- to 60-month-olds. The highest rates, typically over 200 hospitalizations per 100 000 person-years, were in 0- to 6- and 7- to 24-month-old children who were born preterm or with low birth weight, a low 5-minute Apgar score, or birth defects. The hospitalization rate was lower for first-born children at 0 to 6 months but not at older ages. At older ages, hospitalization rates were not substantially different for children whose mothers smoked during pregnancy, but at 0 to 6 months, the rate was higher for children of multiparous nonsmokers than for others. Adjusted rate ratios were elevated across all age categories for several variables, including low birth weight, presence of birth defects, and low 5-minute Apgar. For several others, including preterm birth, maternal multiparity, age 
20 years, and non-Danish/European Union citizenship, adjusted rate ratios were elevated only for 0- to 6-month-olds.
CONCLUSIONS. This large cohort study of hospitalization for childhood pneumococcal disease clarifies the roles of some gestation and birth factors while raising new questions about how these factors work.
Key Words: pneumococcal infections • cohort studies • child • gestational age • birth weight • pregnancy • Denmark
Abbreviations: PD—pneumococcal disease • LBW—low birth weight • RR—rate ratio • ICD—International Classification of Diseases • PY—person-years
Pneumococcal disease (PD)—meningitis, septicemia, pneumonia, and other infections that are caused by Streptococcus pneumoniae—is a leading cause of serious illness and death, causing an estimated 1.6 million deaths worldwide annually, most of them in children.1 Although most children become colonized with S pneumoniae during early childhood,2 for reasons that are not entirely clear, few develop PD. Postnatal risk factors for childhood PD include factors such as out-of-home child care3,4 that likely increase the risk for exposure to pneumococci, as well as factors such as exposure to environmental tobacco smoke,3 and underlying illnesses such as hemoglobinopathies, immune deficiencies, and chronic pulmonary or cardiac disease5 that likely increase the risk for invasion once colonization has occurred. The role of prenatal and perinatal risk factors in susceptibility to childhood PD is incompletely understood. The only controlled study to examine the roles of preterm birth and low birth weight (LBW) in childhood PD reported that they were strongly associated with increased risk. The risk ratio was 1.6 for infants who were born before 38 weeks' gestation and 9.1 for those who were born before 32 weeks; similarly, the rate ratio (RR) was 2.6 for infants who weighed <2500 g at birth and 6.7 for those who weighed <1500 g. This study was limited by a small number of preterm and LBW infants with PD, however.6 Preterm birth, LBW, and maternal smoking during pregnancy have been associated with increased risk for a variety of other infectious outcomes in childhood,7–13 so examining their role in PD may lead to improved understanding of susceptibility and contribute to better prevention of this serious disease. We used data from the Danish National Birth Registry and the hospital discharge registries in western Denmark to conduct a large, population-based, cohort study of the relationship of birth weight, gestational age, maternal smoking during pregnancy, and other factors that are present at birth with subsequent hospitalization for childhood PD.
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METHODS |
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Study Population
The study population consisted of all singleton live births in North Jutland, Aarhus, and Viborg counties (total population: 1.4 million), Denmark, from 1980 through 2001. In this area, pneumococcal conjugate vaccine has never been used for routine childhood vaccination but was available for children with high-risk medical conditions for part of 2001. Since 1968, a unique National Civil Registration number has been assigned to all Danish residents at birth and has been used in all public records, allowing records in various systems to be linked.14,15 For this study, the study population was identified in the Danish National Birth Registry,16,17 disease outcomes were determined from the counties' local hospital discharge registries, and death and emigration were determined from the Danish Civil Registration System, which is updated daily. Because the study was based on de-identified data that were extracted from publicly available records, it was exempt from human subjects review.
Birth Registry Data
Pregnancy- and birth-related data were extracted from the Danish Medical Birth Registry and classified as follows. Gestational age was classified as preterm (37 completed weeks), term (38–41 completed weeks), and postterm (
42 completed weeks). Preterm infants were subclassified as very preterm (31 completed weeks) or moderately preterm (32–36 weeks.) Birth weight was classified as <2500 g, 2500 to 3000 g, 3001 to 3500 g, and >3500 g. Infants with birth weight <2500 g were subclassified as very low birth weight (<2000 g) or moderately low birth weight (2000–2499 g.) Mothers were classified as primiparous or multiparous, and maternal age at delivery as 20 years, 21 to 35 years, and >35 years. Fetal presentation was classified as cephalic or breech/other, and mode of delivery was classified as vaginal, cesarean, or other (including forceps and vacuum extraction). Five-minute Apgar score was classified as low (0–6) or normal (7–10), and birth defects were classified as present or absent. The mother's citizenship was dichotomized as Denmark/original European Union states or any other country, and the infant's county of birth also was recorded. Information on whether the mother smoked during pregnancy, based on self-report at the first antenatal visit, and whether she cohabited with a partner at the time of delivery was available for births that occurred from 1991 through 2001.
Hospital Discharge Registry Data
Information on hospitalizations for PD that occurred through 2004 was obtained from each county's hospital discharge registry, using International Classification of Diseases, Eighth Revision (ICD-8) codes 320.19 (pneumococcal meningitis), 038.29 (pneumococcal septicemia), and 481.xx (pneumococcal pneumonia) before 1994 and ICD-10 codes G00.1 (pneumococcal meningitis), A40.3 (pneumococcal septicemia), and J13.9 (pneumococcal pneumonia) subsequently. Osteomyelitis and arthritis were not included because pathogen-specific ICD codes did not exist for either diagnosis in ICD-8 or for osteomyelitis in ICD-10. Children whose diagnoses were coded as inpatient were considered to have been hospitalized. When >1 of these discharge diagnoses were given during an episode of hospitalization for PD, meningitis had priority over septicemia, which had priority over pneumonia. PD hospitalizations were categorized by the admission date as having occurred at 0 to 6, 7 to 24, 25 to 60, or 61 to 144 months of age. For validation of discharge diagnoses of pneumococcal pneumonia, 31 discharge summaries were selected at random from the 334 available for North Jutland county and reviewed for microbiologic, radiologic, treatment, and clinical information. Patients were considered to have definite PD when a blood culture was positive for S pneumoniae. They were considered to have probable PD when lobar consolidation was present on chest radiograph together with sputum that was culture positive for S pneumoniae and clinical response to penicillin or, in those who previously were treated with antibiotics, clinical response to penicillin alone. They were considered to have possible PD when (1) chest radiography showed consolidation, C-reactive protein was >100 mg/L, and symptoms resolved rapidly with penicillin or (2) radiologic changes were not present but C-reactive protein >100 mg/L, a positive sputum culture for S pneumoniae, and clinical response to penicillin were present.
Civil Registration System Data
Data on emigration and death came from the Civil Registration System.14,15 Follow-up time for each child in the birth cohort was measured from birth to the date of hospital admission for PD; emigration; death; 12th birthday or December 31, 2004, whichever came first.
Statistical Analysis
We excluded records with birth weight <500 g or gestation <25 or >45 completed weeks. We also excluded records with the implausible combination of gestational age <28 weeks and birth weight >2500 g.
For the defined follow-up periods, we computed incidence rates of hospitalization for PD overall and within strata of study variables.18,19 Incidence rates for each type of PD diagnosis (meningitis, septicemia, and pneumonia) were calculated by recording the other 2 diagnoses as nonevents and treating them as censoring variables. We similarly computed incidence rates stratified by both maternal smoking and parity. To examine the joint effects of birth and maternal variables on the risk for hospitalization for PD, we used Poisson regression to model rates of hospitalization for PD at different follow-up times as a function of the birth and maternal variables.20 We analyzed the data with SAS 9.01 (SAS Institute, Inc, Cary, NC).
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RESULTS |
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Descriptive Data
In all, 338633 singleton live births occurred during the study period. After 129 records were excluded (5 with birth weight <500 g, 60 with gestation <25 completed weeks, 48 with gestation >45 completed weeks, 9 with implausible combination of birth weight and gestational age, and 7 that met >1 of the exclusion criteria), 338504 were included in analysis. The median follow-up period was 12.0 years (interquartile range: 7.8–12.0), and the mean was 9.8 years. Table 1 shows characteristics of the study population as well as rates of hospitalization for PD overall and within age categories. No trend toward increasing or decreasing incidence was seen during the study period. In general, this population had a high proportion of normal pregnancies, with 81.5% delivered vaginally, 85.9% delivered at term, 96.2% with birth weight
2500 g, 99.1% with a normal 5-minute Apgar score, and 94.2% with no birth defect noted. For births after 1991, 26.9% of mothers smoked. The prevalence of smoking during pregnancy decreased steadily from 34% in 1991 to 21% in 2001.
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Among the 338 504 children in the study population, 1052 were hospitalized for PD during the follow-up period. Table 1 presents age-specific and overall rates of hospitalization for each PD diagnosis. Pneumonia accounted for the majority of hospitalizations (81.9%), and most hospitalizations occurred at either 7 to 24 months (46.4%) or 25 to 60 months (26.0%).
Stratified Analysis
Table 1 also shows the crude age-specific rate of hospitalization for PD for various strata of birth-related variables. Overall, the rate was highest among 7- to 24-month-olds (97 hospitalizations per 100 000 person-years [PY]), followed by 0- to 6-month-olds (65 hospitalizations per 100 000 PY) and 25- to 60-month-olds (28 hospitalizations per 100 000 PY). Children who were 61 to 144 months of age had the lowest rate, 11 hospitalizations per 100 000 PY. The highest rates were in 0- to 6- and 7- to 24-month-old children who were born preterm (for all preterm births, 212 hospitalizations per 100 000 PY at 0–6 months, 196 at 7–24 months; for very preterm births, 710 hospitalizations per 100 000 PY at 0–6 months, 436 at 7–24 months) or with LBW (for all LBW, 221 at 0–6 months, 214 at 7–24 months; for very low birth weight, 413 at 0–6 months, 275 at 7–24 months), a low 5-minute Apgar score (157 at 0–6 months, 236 at 7–24 months), or birth defects (212 at 0–6 months, 190 at 7–24 months). Table 2, which is restricted to term infants, shows that age-specific PD hospitalization rates were higher in LBW infants independent of preterm birth.
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The PD hospitalization rate was substantially lower for first-born children at 0 to 6 months but not at older ages (Table 1). Rates were higher in all age categories for children whose mothers were
20 years of age at delivery. Rates also were higher in all age categories for children whose mothers lived in North Jutland county during pregnancy. For the subset of children for whom information about maternal smoking was available, the crude rate of hospitalization for PD was lower for children of smokers than of nonsmokers (39 vs 68 cases per 100000 PY) at 0 to 6 months and higher (104 vs 97 hospitalizations per 100000 PY) at 7 to 24 months. This pattern applied only to children with a diagnosis of pneumonia; for those with meningitis or bacteremia, rates were similar regardless of maternal smoking history (data not shown). Table 3, which presents age-specific PD hospitalization data stratified by both maternal smoking and parity, shows that a substantially increased rate of PD hospitalization in 0- to 6-month-olds who were born to nonsmokers was limited to children of multiparous women. Except for maternal smoking, as noted, the patterns that were seen in these stratified analyses did not change when the PD outcome was restricted to diagnoses of septicemia and meningitis (data not shown).
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Regression Analysis
Table 4 presents adjusted RRs from the Poisson regression model including all variables for which data were available for the whole study period. Although confidence intervals were broad, the adjusted RR for hospitalization for PD was elevated in children with LBW in all age categories. Similarly, adjusted RRs were elevated in all age categories for children who were born with birth defects or a 5-minute Apgar score <7 and for those who were born in North Jutland county. For several other variables, including preterm birth, maternal multiparity, age
20 years, and non-Danish/European Union citizenship, RRs were elevated only for 0- to 6-month-olds. A similar model, limited to births from 1991 through 2001 for which data on maternal smoking was available, had results consistent with the stratified and regression analyses presented previously (data not shown).
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Validation of Discharge Diagnosis of Pneumococcal Pneumonia
Among the 31 patients who had a discharge diagnosis of pneumococcal pneumonia and whose discharge summaries were reviewed, 6 (19%) had definite PD, 14 (45%) had probable PD, and 11 (36%) had possible PD.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This large cohort study of hospitalization for childhood PD clarifies the roles of some major gestation and birth factors in conferring risk for hospitalization for PD while raising new questions about how these factors work. Children with preterm birth, LBW, low 5-minute Apgar score, or a birth defect had higher PD hospitalization rates later in infancy and childhood than did children who were born without these factors. These factors, as well as maternal parity and smoking, are discussed further. Other findings—the increased rates in boys, in children of younger mothers, and in children from an area with lower socioeconomic status (North Jutland county)—in this study confirm the results of previous studies8,10,11,21,22 and are not discussed further.
Our study comprised a large population with complete follow-up. The independent and thorough collection of data on predictor and outcome variables and the universal health care system that serves the study population minimize the risk for several types of selection and information bias. In focusing on hospitalizations, we captured the most severe and costly infections. Nevertheless, as is typical for studies that use existing data, we do not have all of the information that we would wish for a comprehensive analysis. Specifically, we do not know which children in our study had comorbid conditions such as congenital heart or lung diseases, immunodeficiency syndromes, or hemoglobinopathies that would have increased their risk for invasive PD. These comorbidities have been reported in only 
7% to 16% of childhood invasive PD in other northern European countries,23,24 however, and they generally are not associated with preterm birth, LBW, or the other birth factors that we studied. Fewer than 20 cases of pediatric HIV infection were reported in the study area during the study period.25 Moreover, invasive PD accounted for a minority of hospitalizations in our study, so it is unlikely that the inclusion of comorbidity data would change our findings in important ways. Similarly, our inability to include diagnoses of uncommon invasive pneumococcal infections such as osteomyelitis, arthritis, and pericarditis is not likely to affect our findings substantially, because these outcomes are so rare.26 Our study relies on discharge diagnoses, which were not confirmed independently. Our validation study, as well as a previous evaluation of the Hospital Discharge Registry System,17 suggests that a discharge diagnosis of PD has reasonably high specificity. However, cases of PD could have been missed if the illness were mild, if cultures were falsely negative, or for other reasons.
Other large studies found that children who are born preterm or with LBW are at greater risk for infectious disease hospitalization and mortality than children who are born at term or with normal birth weight.8–11 Several uncontrolled studies have shown that infants who are born with these risk factors make up a higher proportion of cases of invasive PD in infancy and childhood than might be expected from the relative rarity of these conditions.27–31 We are aware of only 1 other study that compared childhood PD occurrence in preterm and LBW infants with normal infants. In that study, consistent with ours, children who had been born preterm or with LBW had increased risk for invasive PD. That study was not large enough to assess the independent contribution of these factors or their role at various ages, however.6 Our study extends this literature in 2 ways. First, our data clearly demonstrate increased rates of hospitalization for PD in children who were born with either of these risk factors. These rates are increased markedly for children who were born very preterm or with very low birth weight. Second, our data show that, although the effect of these risk factors is most marked in the youngest age groups, increased hospitalization rates for LBW children persist well into childhood.
The increased rates of hospitalization for PD in the first year or so in infants who are born preterm might be expected, given that pneumococcal type–specific antibody is protective and that maternal antibody is transferred across the placenta to the fetus late in gestation. Even in term infants, pneumococcal antibody concentrations32–36 and opsonic activity37,38 usually are lower than in their mothers, and preterm infants have even lower relative levels.32–35,39,40 Preterm infants also may be more likely to be hospitalized than term infants because they are perceived by parents and physicians to be more vulnerable. However, we doubt that either of these reasons fully explains preterm infants' higher rate of hospitalization for PD in the second year of life. The persistently increased rates of hospitalization for PD across all age groups in children with LBW, independent of preterm birth, also are intriguing and not explained easily. The "programming" hypothesis suggests that inadequate prenatal nutrition, manifested as LBW, may affect organ system function permanently, increasing risk for infectious and other diseases later in life.41 Immunologic studies have found decreased transplacental antibody transfer in infants with intrauterine growth retardation as well as impaired immune system function that persisted well into childhood or even adolescence.40,42–44 Epidemiologic studies of other infectious outcomes have had varying results; similar findings for LBW infants were reported from a large Danish case-control study of risk factors for childhood meningococcal disease12 but not from a US study of childhood infectious disease mortality.10 Therefore, our findings suggest that LBW increases both short-term and long-term susceptibility to PD but do not explain how this effect is mediated.
Factors that increase the risk for exposure to S pneumoniae will increase the risk for PD regardless of whether these factors are associated with susceptibility. Of note, in Denmark, most children are cared for at home for the first 6 to 12 months of life. Thereafter, tax-supported child care centers and kindergartens are available for most children, a system that changed little during the study period. Our data show that infants who are born to multiparous women have increased rates of hospitalization for PD at 0 to 6 months of age but not at older ages; infants who are born to multiparous women usually have older siblings, who may increase their risk for exposure to S pneumoniae. This interpretation is supported by the observation that having older siblings is associated with antimicrobial-resistant PD.45 After 6 months of age, most infants and young children likely have substantial contact with other young children, regardless of whether they have siblings. Children with birth defects or low 5-minute Apgar scores also may have increased exposure to S pneumoniae if these children have more contact with the health care system than children without these factors. Of course, these factors also could act by other mechanisms to increase risk.
We found no substantial effect of maternal smoking in older age groups but a considerably higher rate of hospitalization for PD in 0- to 6-month-old infants who were born to multiparous mothers who did not smoke during pregnancy. This finding may be attributable to chance but still merits discussion. This result is surprising, because maternal smoking during pregnancy was associated previously with hospitalization for infectious diseases.7,13 Moreover, women who smoke during pregnancy also are likely to smoke after delivery, and postnatal exposure to environmental tobacco smoke has been associated with childhood invasive PD at all ages.3 However, immunoglobulin levels are higher in pregnant smokers than in nonsmokers,46 suggesting that infants who are born to women who smoked during pregnancy might have higher protective immunoglobulin levels in early life. Because many studies have shown clearly that maternal smoking increases the risk for LBW, among other health issues, and because invasive PD rates in LBW infants are so high, we do not wish to suggest that maternal smoking provides any net benefit to infants.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our most important findings emphasize the heightened risk for hospitalization for PD in children who are born preterm or with LBW, a low 5-minute Apgar score, or a birth defect. For those who are born preterm, rates of PD hospitalization seem to be elevated only in the first 2 years of life, whereas increased hospitalization rates persist for older children who are born with the other risk factors. Our data also suggest that infants who are born to primiparous mothers are relatively protected in early infancy and that the role of maternal smoking during pregnancy may be more complex than previously realized.
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ACKNOWLEDGMENTS |
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This study was supported in part by the Western Danish Research Forum for Health Sciences, Centers for Disease Control and Prevention grant K01 CI000301, and a Ruth L. Kirschstein Individual Predoctoral Fellowship (F31 NS051994).
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FOOTNOTES |
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Accepted Oct 10, 2006.
Address correspondence to Barbara E. Mahon, MD, MPH, Department of Epidemiology, T3E, Boston University School of Public Health, 715 Albany St, Boston, MA 02118. E-mail: mahonbe{at}bu.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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