Abstract

Background The prenatal period may be important for susceptibility to infections. We evaluated whether low birthweight, prematurity, and prenatal maternal smoking were associated with increased risk of invasive meningococcal disease.

Methods We linked the Danish nationwide National Registry of Patients, the Birth Registry, and social registries to obtain data on fetal growth and social factors on 1921 cases of meningococcal disease hospitalized between 1 January, 1980 and 31 December, 1999 (median age 31 months, interquartiles 13–65 months) and 37 451 population controls. The impact of maternal smoking was examined in a subsample of 462 cases and 9240 controls born after 1990, when data on smoking became available in the Birth Registry.

Results The adjusted odds ratios (OR) of meningococcal disease associated with low birthweight (<2500 g) varied between 1.6 (95% CI: 1.1, 2.3) in infants <12 months to 1.5 (95% CI: 1.0, 2.3) in children >60 months of age at hospitalization for meningococcal disease. Premature children had an increased risk of meningococcal disease during the first year of life only (adjusted OR = 1.3, 95% CI: 1.1, 1.9). The effect of low birthweight was very similar among mature and premature children. The adjusted OR for maternal smoking was 1.8 (95% CI: 1.4, 2.2).

Conclusions Low birthweight is associated with an increased risk of meningococcal disease throughout childhood, while an effect of prematurity persists only for 12 months. Maternal prenatal smoking was associated with the risk of meningococcal disease.

Meningococcal disease remains a leading cause of meningitis and septicaemia, particularly in infants, who do not initially produce protective antibodies.1,2 Although the incidence of meningococcal disease decreases after infancy, a subsequent increase is seen during adolescence and early adulthood.3 Invasive disease develops only in a minority colonized with Neisseria meningitidis.3 The mechanisms underlying these epidemiological observations are not clear. Immunity against meningococcal disease is induced by meningoccocal colonization, and cross-reacting antibodies probably play a protective role. Allotypes of mannose binding lectin and complement factor deficiencies constitute risks of meningococcal disease, but these can explain only an uncertain proportion of clinical cases.4

There is increasing evidence that the prenatal and early postnatal periods are important for the development of susceptibility to cardiovascular diseases, diabetes, and cancer.5 Although there are several possible explanations for these associations, particular attention has been given to the programming hypothesis, which postulates that impaired fetal growth may permanently alter organ function.6

There is some evidence that the immune system may be subjected to programming as well. In Gambia, the season of birth has been strongly linked to infectious disease mortality even after the age of 15.7 Prematurity and reduced birth length were reported to be associated with hospitalization due to infectious disease in Danish children up to 12 years of age.8 Maternal smoking is an important determinant of impaired fetal growth, but the same study showed that maternal smoking during pregnancy was associated with a higher risk of hospitalization with infectious diseases, independent of foetal growth indicators.9 To assess whether childhood meningococcal disease has foetal determinants, we determined the risk using population-based data from the Danish National Registry of Patients, the Danish Civil Registration System, the Birth Registry, and social registries.

Methods

Study population and design

We conducted this nationwide registry-based nested case-control study from 1980 to 1999 among all people under 18 years of age, born between 1 January 1980 and 31 December 1996, and living in Denmark. The analysis of the effect of maternal smoking was restricted to children born after 1 January 1991, when data on maternal smoking became available in the Birth Registry.

Cases

We identified patients hospitalized with invasive meningococcal disease by searching in the Danish National Registry of Patients. This registry records 99.9% of all discharges from Danish non-psychiatric acute care hospitals.10 Collected data include the civil registry number, dates of admission and discharge, and up to 20 discharge diagnoses, classified according to the Danish version of the International Classification of Diseases, Eighth Revision (ICD-8) from 1977 to 1993, and the International Classification of Diseases, Tenth Revision (ICD-10) from 1994.10 We included everyone born between 1 January 1980 and 31 December 1996 and listed in the Danish National Registry of Patients from 1980 to 31 December 1999 with a discharge diagnosis of meningococcal disease (ICD-8 codes 036.09, 036.10, 036.11, 036.12, 036.18, 036.19, 036.89, and 036.99 before 1993, and ICD-10 codes A39.0, A39.1, A39.2, A39.3, A39.4, A39.5, A39.8, and A39.9) aged under 18 years at the discharge date.

Controls

All Danish citizens have been registered since 1968 in the Danish Civil Registration System. All births, deaths, immigrations, and emigrations are registered here under the civil registry number unique to every Danish citizen since 1968. From this registry, we selected about 20 controls per case with the same birth month, gender, and year as the cases, who were alive and living in Denmark at the time of the hospitalization for meningococcal disease and who had not been hospitalized before with a diagnosis of meningococcal disease.

We selected this number of controls in order to have a sufficient number of observations in all categories.

Exposure data

We linked the data to the Danish Birth Registry, which contains information on all births in Denmark after 1972 by means of the civil registry number.11 Data on all births are recorded by the midwives and doctors attending deliveries. The main variables in the registry are birthweight, gestational age, birth order, and maternal age. Data about maternal smoking at the first antenatal visit have been available since 1991. From the administrative social registries (House Registry, Tax Registry) in Statistics Denmark, and by means of the civil registry number, we retrieved family data on crowding (< or >40 m2 per person in the residence), and household income per capita in the family, since these factors have been associated with meningococcal disease in other studies.3,12–14

Statistical analysis

We used conditional logistic regression to estimate odds ratios (OR) and 95% Wald CI for estimating meningococcal disease in relation to birthweight and prematurity after adjustment for maternal age, birth order, per capita income, crowding, and calendar year of hospitalization. In the subanalysis with a focus on maternal smoking, data on smoking recorded at the first antenatal visit were included in the models, with non-maternal smoking as the reference group. We used the likelihood ratio test to evaluate the homogeneity. The analyses were performed with SAS 8.01.

Results

Our study criteria were met by 1921 cases of meningococcal disease and 37 451 controls, and 462 cases (192 with mothers who smoked) and 9240 controls (2446 with mothers who smoked) were included in the analysis of smoking. Table 1 shows the distribution of the study variables and potential confounders. More cases (7.7%) than controls (5.2%) had low birthweight, but similar proportions of children were premature. Some 422 of the cases were aged 0–12 months, 1059 13–60 months, and 440 >60 months at the time for hospitalization for meningococcal disease. Table 2 shows the relative risk of meningococcal disease according to birthweight after adjustment for prematurity and other possible confounding factors. To reduce the statistical instability and improve the precision, we combined birthweight categories with similar risk estimates. The overall OR was 1.4 (95% CI: 1.2, 1.7). We found a persistent effect of low birthweight on the risk of meningococcal diseases in all age groups, with adjusted OR between 1.4 and 1.6. We also found a reduced risk of meningococcal disease infection in the first year of life for children with a birthweight of >3500 g (adjusted OR = 0.7, 95% CI: 0.6, 0.9).

Table 1

Descriptive data for meningococcal disease cases and controls

 Cases  Controls  
Variables
 
N = 1921
 
(%)
 
N = 37 451
 
(%)
 
Birthweight (g)     
    <2500 147 7.7 1930 5.1 
    2500–3000 280 14.6 4891 13.1 
    3001–3500 686 35.7 12 644 33.8 
    >3500 796 41.4 17 724 47.3 
    Missing 12 0.6 262 0.7 
Gestational age (weeks)     
    Premature (<37 weeks) 123 6.4 1837 4.9 
    Full term (≥37 weeks) 1745 90.8 34 418 91.9 
    Missing 53 2.8 1196 3.2 
Birth order     
    1 886 46.1 16 993 45.4 
    >1 1035 53.9 20 458 54.6 
Maternal age (years)     
    <24 551 28.7 7937 21.2 
    24–27 442 23.0 8874 23.7 
    28–30 403 21.0 8831 23.6 
    >30 525 27.3 11 798 31.5 
    Missing 11  0.1 
Per capita income (DKK)     
    <26 900 653 34.0 9091 24.3 
    26 901–53 800 483 25.1 9347 25.0 
    53 801–82 200 408 21.2 9410 25.2 
    >82 200 365 19.0 9381 25.0 
    Missing 12 0.7 222 0.5 
Crowding (m2 per person)     
    ≥40 1162 60.5 20 643 55.1 
    <40 758 39.5 16 768 44.8 
    Missing — 40 0.1 
 Cases  Controls  
Variables
 
N = 1921
 
(%)
 
N = 37 451
 
(%)
 
Birthweight (g)     
    <2500 147 7.7 1930 5.1 
    2500–3000 280 14.6 4891 13.1 
    3001–3500 686 35.7 12 644 33.8 
    >3500 796 41.4 17 724 47.3 
    Missing 12 0.6 262 0.7 
Gestational age (weeks)     
    Premature (<37 weeks) 123 6.4 1837 4.9 
    Full term (≥37 weeks) 1745 90.8 34 418 91.9 
    Missing 53 2.8 1196 3.2 
Birth order     
    1 886 46.1 16 993 45.4 
    >1 1035 53.9 20 458 54.6 
Maternal age (years)     
    <24 551 28.7 7937 21.2 
    24–27 442 23.0 8874 23.7 
    28–30 403 21.0 8831 23.6 
    >30 525 27.3 11 798 31.5 
    Missing 11  0.1 
Per capita income (DKK)     
    <26 900 653 34.0 9091 24.3 
    26 901–53 800 483 25.1 9347 25.0 
    53 801–82 200 408 21.2 9410 25.2 
    >82 200 365 19.0 9381 25.0 
    Missing 12 0.7 222 0.5 
Crowding (m2 per person)     
    ≥40 1162 60.5 20 643 55.1 
    <40 758 39.5 16 768 44.8 
    Missing — 40 0.1 
Table 2

Risk of invasive meningococcal disease according to birthweight and age at hospitalizationa

 Age at hospitalization   
 0–12 months 13–60 months >60 months 
Birthweight (g)
 
ORb (95% CI)
 
OR (95% CI)
 
OR (95% CI)
 
<2500c 1.6 (1.1, 2.3) 1.4 (1.0, 2.1) 1.5 (1.0, 2.3) 
2500–3500 1 (ref.) 1 (ref.) 1 (ref.) 
>3500d 0.7 (0.6, 0.9) 1.0 (0.9, 1.2) 1.1 (0.9, 1.3) 
 Age at hospitalization   
 0–12 months 13–60 months >60 months 
Birthweight (g)
 
ORb (95% CI)
 
OR (95% CI)
 
OR (95% CI)
 
<2500c 1.6 (1.1, 2.3) 1.4 (1.0, 2.1) 1.5 (1.0, 2.3) 
2500–3500 1 (ref.) 1 (ref.) 1 (ref.) 
>3500d 0.7 (0.6, 0.9) 1.0 (0.9, 1.2) 1.1 (0.9, 1.3) 
a

Adjusted for gestational age, parity (or birth order), maternal age, family per capita income, calendar year, and crowding.

b

Odds ratio.

c

P = 0.51 by the test for homogeneity across age of hospitalization for meningococcal disease.

d

P = 0.0007 by the test for homogeneity across age of hospitalization for meningococcal disease.

Table 3 shows a 30% increased risk of meningococcal disease during the first 12 months of life associated with prematurity (adjusted OR = 1.3, 95% CI: 1.1, 1.9). The relative risk decreased to 0.9 (95% CI: 0.7, 1.1) and 0.8 (95% CI: 0.6, 1.1) for infection after 12 and 60 months of age, respectively.

Table 3

Risk of invasive meningococcal disease according to age at hospitalizationa

 Age at hospitalization   
 0–12 months 13–60 months >60 months 
Gestational age (weeks)
 
ORb (95% CI)
 
OR (95% CI)
 
OR (95% CI)
 
<37c 1.3 (1.1, 1.9) 0.9 (0.7, 1.1) 0.8 (0.6, 1.1) 
≥37 (reference) 1 (ref.) 1 (ref.) 1 (ref.) 
 Age at hospitalization   
 0–12 months 13–60 months >60 months 
Gestational age (weeks)
 
ORb (95% CI)
 
OR (95% CI)
 
OR (95% CI)
 
<37c 1.3 (1.1, 1.9) 0.9 (0.7, 1.1) 0.8 (0.6, 1.1) 
≥37 (reference) 1 (ref.) 1 (ref.) 1 (ref.) 
a

Adjusted for birthweight, gender, parity (or birth order), maternal age, family per capita income, calendar year, and crowding.

b

Odds ratio.

c

P = 0.0005 by the test for homogeneity across age of hospitalization for meningococcal disease.

Table 4 shows the effect of gestational age on the relative risk associated with low birthweight. The estimates for low birthweight were almost identical for mature (adjusted OR = 1.3, 95% CI: 1.0, 1.7) and premature children (adjusted OR = 1.5, 95% CI: 1.2, 1.8).

Table 4

Risk of invasive meningococcal disease in children with low birthweight stratified according to prematurity (<37 weeks)a

 Premature Mature 
Birthweight (g)
 
ORb(95% CI)
 
OR (95%CI)
 
<2500c 1.5 (1.2, 1.8) 1.3 (1.0, 1.7) 
≥2500 (reference) 1 (ref.) 1 (ref.) 
 Premature Mature 
Birthweight (g)
 
ORb(95% CI)
 
OR (95%CI)
 
<2500c 1.5 (1.2, 1.8) 1.3 (1.0, 1.7) 
≥2500 (reference) 1 (ref.) 1 (ref.) 
a

Adjusted for parity (or birth order), maternal age, family per capita income, calendar year, and crowding.

b

Odds ratio.

c

P = 0.77 by the test for homogeneity.

The subanalysis confirmed that maternal smoking was associated with an increased risk of meningococcal disease, independent of fetal growth parameters and social variables (adjusted OR = 1.8, 95% CI: 1.4, 2.2). The adjusted risk estimates for low birthweight and prematurity in the subanalysis were 1.2 (95% CI: 0.8, 1.7) and 1.2 (95% CI: 0.7, 2.0), respectively. In this subanalysis, the small number of subjects prevented us from conducting an analysis stratified by age at hospitalization. In a subanalysis we found, essentially, the same risk estimates for low birthweight and prematurity when we excluded maternal smoking from the logistic regression model with OR of 1.3 (95% CI: 0.8, 1.8) and 1.2 (95% CI: 0.7, 2.1), respectively.

Discussion

This nationwide analysis of more than 1900 cases of meningococcal disease suggests that low birthweight increases the risk of invasive meningococcal disease. The effect of pre- maturity was not detectable after the first year of life. We found a strong association between a prenatal record of maternal smoking and risk of meningococcal disease in early childhood, an effect that was independent of fetal growth and prematurity.

The biological mechanisms behind the observations are not clear. One possibility is that programming of the immune system may play a role in modifying the risk of meningococcal disease. The associations with reduced fetal growth were not explained by the effect of gestational age. Both pre- and postnatal maternal lifestyle may also have some impact on the risk, since it has recently been shown that maternal prenatal lifestyle factors are associated with hospitalization for infectious disease after adjustment for fetal growth indicators.8,9 Prenatal undernutrition has been linked to cell-mediated immunity, which seems to play an important role in protecting against meningococcal disease,15 involution of thymus, and antibody response to vaccination.16–19 It is well known that humoral immunity, and some genetic immune defects are important factors for susceptibility to meningococcal disease.3 For example, variants of the gene for mannose-binding lectin seem to have an impact on susceptibility to meningococcal disease.20 Furthermore, mannose-binding lectin insufficiency plays an important role in the host defence against acute respiratory tract infection during the period from 6 to 17 months.21

The strengths of our study include the complete follow-up, and detailed adjustment for social confounders at family level, and data on maternal smoking. In spite of its large size, some risk estimates were imprecise. Furthermore, there was independent classification of both exposure and outcome data from a nationwide uniformly organized health care system, a feature that allowed a population-based design. However, it is a well-known fact that discharge diagnoses are not entirely accurate.22 Meningococcal disease is registered with high validity.23 However, cases registered with meningococcal disease may have been misclassified in 5 to 10% of the cases listed in the Danish Registry of Patients. This lack of specificity may have led us to underestimate the risk of meningococcal disease associated with low birthweight and prematurity. The data in the Birth Registry24 have proven to be of high quality, and major confounding factors were accounted for in the analyses. However, we lacked data on postnatal growth.

We have confirmed a recent finding from a retrospective cohort study from the US, which states that smoking during pregnancy is a risk factor for invasive meningococcal disease.25 We were unable to separate a prenatal from a passive smoking effect in late childhood. Both smoking and passive smoking have been reported as risk factors for meningococcal disease in some studies.11–15,26,27 However, there are some indications that the influence of maternal smoking on admission for infections is mainly through a prenatal effect.28

In summary, we found that low birthweight has long-term consequences for susceptibility to meningococcal disease in childhood and early adulthood, and that maternal smoking is a risk factor for meningococcal disease.

KEY MESSAGES

  • Low birthweight is associated with an increased risk of meningococcal disease throughout childhood.

  • Prematurity is associated with an increased risk of meningococcal disease during the first year of life.

  • Maternal smoking during pregnancy is also associated with an increased risk of meningococcal disease.

The study is supported by the Western Danish Research Forum for Health Sciences (Vestdansk Forskningsforum). The National Centre for Register-based Research is supported financially by the Danish National Research Foundation.

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