Importance To our knowledge, no previous study has examined functioning in adult life among persons who had bacterial meningitis in childhood.
Objective To study educational achievement and economic self-sufficiency in adults diagnosed as having bacterial meningitis in childhood.
Design, Setting, and Participants Nationwide population-based cohort study using national registries of Danish-born children diagnosed as having meningococcal, pneumococcal, or Haemophilus influenzae meningitis in the period 1977-2007 (n=2784 patients). Comparison cohorts from the same population individually matched on age and sex were identified, as were siblings of all study participants. End of study period was 2010.
Main Outcomes and Measures Cumulative incidences of completed vocational education, high school education, higher education, time to first full year of economic self-sufficiency, and receipt of disability pension and differences in these outcomes at age 35 years among meningitis patients, comparison cohorts, and siblings.
Results By age 35 years, among persons who had a history of childhood meningococcal (n=1338), pneumococcal (n=455), and H influenzae (n=991) meningitis, an estimated 11.0% (41.5% vs 52.5%; 95% CI, 7.3%-14.7%), 10.2% (42.6% vs 52.8%; 95% CI, 3.8%-16.6%), and 5.5% (47.7% vs 53.2%; 95% CI, 1.9%-9.1%) fewer persons, respectively, had completed high school and 7.9% (29.3% vs 37.2%; 95% CI, 1.6%-14.2%), 8.9% (28.1% vs 37.0%; 95% CI, 0.6%-17.2%), and 6.5% (33.5% vs 40.0%; 95% CI, 1.4%-11.6%) fewer had attained a higher education compared with individuals from the comparison cohort. Siblings of meningococcal meningitis patients also had lower educational achievements, while educational achievements of siblings of pneumococcal and H influenzae meningitis patients did not differ substantially from those in the general population. At end of follow-up, 3.8% (90.3% vs 94.1%; 95% CI, 1.1%-6.5%), 10.6% (84.0% vs 94.6%; 95% CI, 5.1%-16.1%), and 4.3% (90.6% vs 94.9%; 95% CI, 2.0%-6.6%) fewer meningococcal, pneumococcal, and H influenzae meningitis patients were economically self-sufficient and 1.5% (3.7% vs 2.3%; 95% CI, −0.2% to 3.2%), 8.7% (10.0% vs 1.3%; 95% CI, 5.0%-12.4%), and 3.7% (6.2% vs 2.5%; 95% CI, 1.6%-5.8%) more received disability pension compared with individuals from the comparison cohort.
Conclusions and Relevance In a Danish population, bacterial meningitis in childhood was associated with lower educational achievement and economic self-sufficiency in adult life. This association may apply particularly to pneumococcal and H influenzae meningitis, whereas for meningococcal meningitis the lower educational achievement may be family-related.
Short- and long-term mortality in children diagnosed as having bacterial meningitis have been well described.1-4 The infection may lead to brain damage due to inflammation, infarction, or seizures causing neuronal necrosis,5 and survivors of childhood bacterial meningitis are at particular risk of hearing loss, seizure disorders, motor deficits, and cognitive impairment.6 Learning disabilities are well documented as sequelae of the disease,7 with implications for educational achievement in adolescence.8
To our knowledge, no previous study has examined functioning in adult life among persons diagnosed as having bacterial meningitis in childhood. We therefore aimed to estimate educational achievement and economic self-sufficiency among children surviving bacterial meningitis on a population-based, nationwide scale compared with the general population. To elucidate the potential association with family-related factors, we compared the outcomes of the patients with that of their siblings and further estimated the educational achievement of the parents of members of the patient and comparison cohorts.
We used 4 nationwide, population-based cohorts identified from Danish registries: (1) all patients who in the period 1977-2007 and before age 12 years had diagnoses of bacterial meningitis due to Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae and survived to age 13 years; (2) a comparison cohort from the general population individually matched on date of birth and sex; (3) full siblings of the meningitis patients; and (4) full siblings of persons in the population comparison cohort. The outcomes were time from age 13 years to (1) completion of vocational education, (2) completion of high school, (3) completion of higher education, (4) first full year of economic self-sufficiency from personal income, and (5) first year an individual received disability pension.
Cumulative incidence of these outcomes and differences between the cohorts in cumulative incidence at age 35 years were measured. The cumulative incidence curve by age summarizes the age-specific prevalences of the outcomes to age 35 years.
The population of Denmark younger than age 12 years was 893 650 on January 1, 1977, and 790 691 on January 1, 2010.9 In the study period, N meningitidis, S pneumoniae, and H influenzae were the most frequent etiologies of bacterial meningitis in children, and more than 80% of bacterial meningitis cases in Denmark were due to these 3 bacteria.10,11 During this period, tax-supported medical care and education were available to all Danish residents.
We used the unique 10-digit personal identification number (PIN) assigned to all Danish citizens at birth or immigration to avoid multiple registrations and to track individuals in the following registries, described in detail in eAppendix 1.
From the Danish National Registry of Patients (DNRP) we extracted the first date of any meningococcal, pneumococcal, or H influenzae meningitis diagnosis for each patient.12 Study participants diagnosed as having intrauterine and birth asphyxia or chromosomal abnormalities (International Statistical Classification of Diseases, 8th Revision [ICD-8 ] and 10th Revision [ICD-10 ] codes specified in eAppendix 2) were also identified from this registry.
From the Danish Civil Registration System, the population comparison cohort and siblings and parents of the patients and population comparison cohort members were identified.13,14 From this registry, we also extracted data on birth, sex, date of immigration/emigration, loss to follow-up, and date of death of all study participants.
From the Danish Medical Birth Registry, we extracted information on birth weight, gestational age at birth, and 5-minute Apgar score.15
From the Danish Educational Attainment Registry, Statistics Denmark, we extracted data on the highest educational achievement obtained by the study population in each calendar year during the study period.16,17 In total, 97% of the ethnic Danish population has nonmissing education information in the registry, with an estimated misclassification of 0% to 3%.17
From the Employment Classification Module, Statistics Denmark, we extracted the first date an individual was registered as economically self-sufficient from personal income and the first date an individual received disability pension.18-20 In the registry, an individual is registered as economically self-sufficient when his or her main income for a full year stems from either business profit or employment (described in eAppendix 1).
The study was approved by the Danish Data Protection Agency. Ethics approval and individual consent are not required by Danish legislation governing this type of study.
Cohort of Meningitis Patients. We used the DNRP to identify all patients who (1) were registered with a diagnosis of meningococcal, pneumococcal, or H influenzae meningitis (ICD-8 and ICD-10 codes specified in eAppendix 3) for the first time during the period January 1, 1977, to January 1, 2007 (January 1, 1997, for H influenzae meningitis patients); (2) had diagnoses before age 12 years (before age 5 years for H influenzae meningitis patients, as the majority of childhood H influenzae meningitis cases occur before age 5 years21); (3) were born in Denmark during the period January 1, 1975, to January 1, 1997 (January 1, 1990, for H influenzae meningitis patients); and (4) were not diagnosed as having any other neuroinfection (as specified in eAppendix 4) before diagnosis of bacterial meningitis. The H influenzae type b conjugate vaccine was introduced into the Danish childhood vaccination program on June 1, 1993.22 Thus, we did not include H influenzae meningitis patients with diagnoses later than December 31, 1996, or born after January 1, 1990, as we consider them a selected population. The 7-valent conjugated pneumococcal vaccine was not introduced into the Danish childhood vaccination program until October 1, 2007,23 and meningococcal vaccine has never been included. Patients were excluded from the study if they died, emigrated, or were lost to follow-up before age 13 years.
Population Comparison Cohort. Individuals in the population comparison cohorts were individually matched. From the Danish Civil Registration System, we identified for each meningitis patient all Danish citizens who were born on the same date and were the same sex as the patient and were alive and not diagnosed as having meningitis before age 13 years. From this population, we randomly chose 4 individuals for the comparison cohort.
Sibling Cohorts. To take into account potential confounding from family-related factors, we used the Danish Civil Registration System to identify all full siblings of both meningitis patients and individuals from the population comparison cohort who were born in the period January 1, 1975, to January 1, 1997 (January 1, 1990, for siblings of H influenzae meningitis patients and the corresponding comparison cohort) and alive and living in Denmark at age 13 years.
Parents of the Study Population. We used the Danish Civil Registration System to identify all parents of the meningitis patients and members of the population comparison cohort.
We measured the time intervals from age 13 years to the first date the individual was registered (1) as having completed vocational education or training (eg, carpenter, dental technician, hairdresser); (2) as having completed high school education (completing the 12th school year); (3) as having completed higher education (obtaining a degree from an institution of higher education; eg, college or university); (4) as economically self-sufficient; and (5) as having received disability pension. In Denmark, completing high school is required for higher education but not for vocational education. In all cohorts, less than 2% had no information on educational achievements, and these individuals were classified in the analyses as having no education other than elementary school.
Observation time was calculated from age 13 years to 1 of the above mentioned outcomes, death, emigration, loss to follow-up, age 35 years, or October 1, 2010, whichever came first. Because most people in Denmark finish their higher education between ages 25 and 30 years, we continued follow-up through age 35 years for each person. For meningitis patients, persons in the population comparison cohort, and siblings, we calculated cumulative incidence of the outcomes, taking into account losses due to death and emigration, and because all individuals were included starting at the same age (13 years), the cumulative incidence function also describes the age-specific prevalence rates.
We calculated the differences between the prevalences at age 35 years for patients vs members of the population comparison cohort, patients vs their siblings, and siblings of patients vs siblings of the comparison cohorts. The analyses were performed separately for patients with meningococcal, pneumococcal, and H influenzae meningitis and members of their respective population comparison cohorts and sibling cohorts. Two subanalyses were performed: (1) excluding all individuals in the study population diagnosed as having low birth weight, premature birth, intrauterine and birth asphyxia, a 5-minute Apgar score less than 7, and chromosomal abnormalities and (2) stratifying by birth before and after January 1, 1980.
In a cross-sectional analysis, the educational achievements of parents of meningitis patients and individuals in the population comparison cohort were assessed 1 year before the diagnosis date of bacterial meningitis in the patient population. SPSS, version 19 (IBM Inc), and R software, version 2.14.2, were used for data analysis.
We identified 2924 patients who met the inclusion criteria: 1391 patients with meningococcal meningitis, 496 with pneumococcal meningitis, and 1037 with H influenzae meningitis. Fifty-three patients (3.8%) with meningococcal meningitis, 41 (8.3%) with pneumococcal meningitis, and 39 (3.8%) with H influenzae meningitis had died, 6 had emigrated, and 1 was lost to follow-up before age 13 years, leaving a total of 2784 patients and 11 136 members of the population comparison cohort in the study (Table 1 and Figure 1).
Time to completion of vocational education, high school, and higher education are shown in Figure 2. Number of events in the study population and total observation time are shown in eTable 1. Among meningococcal meningitis patients, an estimated 11.0% fewer (41.5% vs 52.5%; 95% CI, 7.3%-14.7%) had completed high school and 7.9% fewer (29.3% vs 37.2%; 95% CI, 1.6%-14.2%) had obtained a higher education by age 35 years compared with members of the population comparison cohort (Table 2). The educational achievement of the meningococcal meningitis patients did not differ substantially from that of their siblings. Of note, by age 35 years an estimated 13.0% fewer siblings of meningococcal meningitis patients (41.1% vs 54.1%; 95% CI, 9.4%-16.6%) had completed high school and 4.6% fewer (32.9% vs 37.5%; 95% CI, −2.0% to 11.2%) had obtained a higher education than siblings of the population comparison cohort.
We observed no substantial difference between pneumococcal meningitis patients and members of the population comparison cohort in estimated proportions completing a vocational education at age 35 years (Figure 2 and Table 2). By age 35 years, an estimated 10.2% fewer (42.6% vs 52.8%; 95% CI, 3.8%-16.6%) and 8.9% fewer (28.1% vs 37.0%; 95% CI, 0.6%-17.2%) pneumococcal meningitis patients had completed high school and higher education compared with members of the population comparison cohort. A lower proportion of pneumococcal meningitis patients had completed high school and higher education compared with their siblings. In contrast, no substantial differences were observed between the 2 cohorts of siblings.
Among H influenzae meningitis patients, 5.5% fewer (47.7% vs 53.2%; 95% CI, 1.9%-9.1%) had completed high school and 6.5% fewer (33.5% vs 40.0%; 95% CI, 1.4%-11.6%) had completed higher education by age 35 years compared with members of the population comparison cohort; compared with their siblings, 5.5% fewer (47.7% vs 53.2%; 95% CI, 0.8%-10.2%) and 7.9% fewer (33.5% vs 41.4%; 95% CI, 1.4%-14.4%) had attained these education levels (Figure 2 and Table 2). No substantial differences in educational achievements were observed between the 2 cohorts of siblings.
One year before diagnosis of meningococcal meningitis, parents of the patients had lower educational achievements than parents of members of the population comparison cohort (Table 3). The educational achievements of parents of pneumococcal and H influenzae meningitis patients did not differ substantially from those of the parents of members of the corresponding population comparison cohorts.
Economic Self-sufficiency and Disability Pension
At end of follow-up, an estimated 3.8% (90.3% vs 94.1%; 95% CI, 1.1%-6.5%), 10.6% (84.0% vs 94.6%; 95% CI, 5.1%-16.1%), and 4.3% (90.6% vs 94.9%; 95% CI, 2.0%-6.6%) fewer meningococcal, pneumococcal, and H influenzae meningitis patients had been economically self-sufficient compared with the individuals from the comparison cohort, and 1.5% (3.7% vs 2.3%; 95% CI, −0.2% to 3.2%), 8.7% (10.0% vs 1.3%; 95% CI, 5.0%-12.4%), and 3.7% (6.2% vs 2.5%; 95% CI, 1.6%-5.8%) more patients received disability pension (eFigure 1 and Table 2).
A subanalysis in which individuals diagnosed as having underlying neonatal conditions were excluded yielded almost the same estimates as obtained in the analyses including all study participants, except for the estimated prevalence of disability pension at age 35 years in pneumococcal meningitis patients, which was 6.1% (95% CI, 3.6%-9.6%) (eTable 2). We observed no substantial differences in risk estimates in patients born before and after January 1, 1980 (eFigure 2 and eFigure 3).
To our knowledge, this is the first study to describe on a national scale the achievements of adults who were diagnosed as having bacterial meningitis in childhood. In almost 3000 children, a diagnosis of meningococcal, pneumococcal, or H influenzae meningitis was associated with lower educational levels than in the general population. In contrast to siblings and parents of pneumococcal and H influenzae meningitis patients, siblings and parents of meningococcal meningitis patients also had lower educational achievements. In addition, the associations between childhood pneumococcal and H influenzae meningitis diagnoses and receiving disability pension suggest that these conditions affect functioning in adult life.
The meningococcal meningitis patients achieved educational levels comparable with that of their siblings, indicating that the lower level of education in these patients may stem from factors not directly related to the meningitis episode. Low birth weight and prematurity are well-established risk factors for adolescent learning difficulties24-26 and have been shown to be associated with an increased risk of meningococcal disease in childhood.27 Still, our results suggest that family-related factors are associated with the low educational achievements in the meningococcal meningitis cohort after excluding individuals diagnosed as having low birth weight and prematurity from the analyses. The lower level of education among parents of meningococcal meningitis patients further suggests that family-related factors are associated with the low educational achievements in this patient group.
In contrast, siblings of patients with pneumococcal meningitis and H influenzae meningitis achieved educational levels comparable with those of members of the population comparison cohort and their siblings. This finding implies that the lower level of education achieved among pneumococcal and H influenzae meningitis patients may stem from neurocognitive deficits induced by the meningitis episode. The observation of equivalent educational achievements among parents of pneumococcal and H influenzae meningitis patients and the parents of members of the population comparison cohort further supports the conclusion that educational deficits in these 2 meningitis groups are not attributable to family-related factors.
Learning, memory, and behavioral difficulties are well described among survivors of childhood bacterial meningitis7,28-30 and have been shown to affect subsequent educational achievements in adolescents.8 An English study reported that more than a quarter of 461 children who had bacterial meningitis in infancy in 1985-1987, compared with 6.6% of those who did not, failed all national examinations at age 16 years. Of the children who had had meningitis, 7.8% attended special schools compared with none in the comparison group. Because the study recruited age- and sex-matched controls from the panels of the same general practitioners, it did not take into account socioeconomic confounding. Among case patients who attended special schools, 31% had been infected with H influenzae and 22% had had meningitis due to Escherichia coli. No further stratification by bacterial etiology was reported.8
Children with pneumococcal meningitis are at higher risk of developing disabling sequelae than children with meningococcal meningitis and, to a lesser extent, those with H influenzae meningitis.5,6 A recent study on sequelae following pneumococcal meningitis in childhood with a median follow-up of 6 years revealed lower full-scale IQ, verbal IQ, and numeracy in patients compared with controls, who were siblings or neighbors of the same age.31 Learning and memory impairments following an episode of pneumococcal meningitis are likely explained by the virulence of the pneumococcus bacterium.32
Maternal smoking is associated with an increased risk of meningococcal disease.33,34 As well, variation in meningococcal disease burden among geographic and socioeconomic subgroups has been described, revealing an increased incidence of meningococcal disease in areas of social deprivation.35,36 The socioeconomic pattern of meningococcal disease incidence accords with our finding of lower educational achievement among siblings and parents of meningococcal meningitis patients compared with the general population. Social deprivation in families of meningococcal meningitis patients thereby seems to be a strong predictor for their eventual lower educational status—even stronger than the meningococcal meningitis episode itself.
The major strengths of the present study are its large size, its population-based design, and its nearly complete and long-term follow-up. The Danish Civil Registration System enabled us to identify a large population-based comparison cohort well matched in terms of sex, age, and country of birth. To account for confounding from family-related factors, we identified siblings and parents of patients and members of the population comparison cohort. The Danish Educational Attainment Registry made it possible to obtain almost complete educational status at multiple points during a 30-year period and access to data on economic self-sufficiency and disability pension allowed us to determine whether the meningitis episodes were associated with adverse economic outcomes.
Possible study limitations include reliance on registry-based discharge diagnoses, which may be inaccurate and incomplete. However, the registration of meningococcal meningitis in the DNRP has been shown to be highly sensitive and specific,37,38 making it reasonable to assume similar high sensitivities and specificities for the pneumococcal and H influenzae meningitis diagnoses. We did not have access to clinical and laboratory data obtained during hospitalizations. Furthermore, we were not able to access data on individual-level school grades, special educational needs, or number of failed examinations during the study period.
A diagnosis of meningococcal, pneumococcal, or H influenzae meningitis in childhood is associated with lower educational achievement and economic self-sufficiency in adult life. This association may apply particularly to pneumococcal and H influenzae meningitis, whereas for meningococcal meningitis the lower educational achievement may be family related. Our study suggests that children diagnosed as having pneumococcal or H influenzae meningitis may benefit from follow-up into adulthood to identify those who could potentially benefit from psychosocial support.
Corresponding Author: Casper Roed, MD, Department of Infectious Diseases, Copenhagen University Hospital, Blegdamsvej 9, DK2100 Copenhagen, Denmark (casper.roed@rh.regionh.dk; casperroed@hotmail.com).
Author Contributions: Dr Roed had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Roed, Omland, Sorensen, Obel.
Acquisition of data: Roed.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: Roed, Rothman, Obel.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Roed, Omland, Rothman, Obel.
Obtained funding: Roed, Obel.
Administrative, technical, or material support: Roed, Obel.
Study supervision: Roed, Omland, Skinhoj, Sorensen, Obel.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: The work was supported by the Faculty of Health Sciences, Copenhagen University, and the NOVO Nordisk Foundation.
Role of the Sponsor: The funders had no role in the study design; in collection, management, analysis, and interpretation of data; in the preparation, review, or approval of the manuscript; or in the decision to submit the article for publication.
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