Articles
Association of gestational age and growth measures at birth with infection-related admissions to hospital throughout childhood: a population-based, data-linkage study from Western Australia

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Summary

Background

Reduced gestational age and low birthweight are associated with an increased risk of neonatal infections. However, the long-term risk of infection, especially in late preterm infants or those at near-normal birthweight, is unknown. We estimated whether rates of infection-related admissions to hospital for children in Western Australia were associated with age, gestational age, birthweight, and birth length.

Methods

We did a population-based, data-linkage study using total-linked, registry data from the Western Australia Birth Register of all liveborn, non-Indigenous Australian singleton births recorded from Jan 1, 1980, to Dec 31, 2010. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked to data about subsequent admissions to hospital or death registrations. Gestational age was assessed from both the last menstrual period and from estimates based on ultrasonography. We categorised birthweight by 500 g bands and birth length by 5 cm bands, and approximated the reference ranges for both to the 50th percentile. Because size at birth and gestational age are strongly associated, we calculated Z scores for gestational-specific and sex-specific birthweight, birth length, and ponderal index. Our primary outcomes were the number and type of infection-related admissions to hospital. We used multilevel negative binomial regression to generate rate ratios (RR) for such admissions, identified by codes from the International Classification of Diseases, versions 9 and 10-AM. We adjusted the RRs for maternal age at delivery, birth year, birth season, parity, sex, 5-min Apgar score, delivery method, socioeconomic status, and bronchopulmonary dysplasia.

Findings

Of 719 311 liveborn singletons included in the analysis and followed up for 8 824 093 person-years, 365 867 infection-related admissions to hospital occurred for 213 683 (30%) children. Of the 719 311 children included in the analysis, 137 124 (19%) had one infection-related admission to hospital, 43 796 (6%) had two, 16 679 (2%) had three, and 16 084 (2%) had four or more. The 365 867 admissions to hospital included a diagnosis of infection of the upper respiratory tract for 174 653 (48%), the lower respiratory tract for 74 297 (20%), the gastrointestinal tract for 44 755 (12%), and a viral infection for 37 213 (10%). Infection-related rates of admissions to hospital increased by 12% for each week reduction in gestational age less than 39–40 weeks (RR 1·12, 95% CI 1·12–1·13), by 19% for each 500 g reduction in birthweight less than 3000–3500 g (1·19, 1·18–1·21), and by 41% for each 5 cm reduction in birth length less than 45–50 cm (1·41, 1·38–1·45). Gestational age-specific and sex-specific birthweight Z scores lower than the 25th to 50th percentile and birth length Z scores lower than the 10th to 25th percentile were associated with increased rates of infection-related admissions to hospital (eg, 1st–5th percentile RR 1·15, 95% CI 1·12–1·19, and 1·11, 1·07–1·14, respectively). Ponderal index Z scores lower than the 25th to 50th percentile were also associated with increased rates of infection-related admissions (eg, 1st–5th percentile RR 1·08, 95% CI 1·04–1·12). A gestational age of 41 weeks or later, a birthweight or birth length Z score above the 50th percentile, or a ponderal index Z score between the 75th and 95th percentile, were associated with modestly reduced rates of infection-related admissions to hospital.

Interpretation

Children who were born with reduced gestational age, birthweight, and birth length have persistently increased rates of infection-related admissions to hospital until age 18 years. Pregnancy outcomes should be optimised to prevent infection occurring in this population, especially in resource-limited settings where suboptimum intrauterine growth and moderate prematurity are common.

Funding

Australian National Health and Medical Research Council.

Introduction

Survival of very preterm and low-birthweight infants has improved substantially, especially in resource-rich settings in the past two to three decades, but less is known about longer-term health outcomes for these individuals, especially in those born late preterm (weeks+days: 34–36+6 weeks gestational age), early term (37+0 weeks–38+6 weeks gestational age), or of near-normal birthweight (2500–3000 g). Suboptimum intrauterine growth (reduced birthweight and birth length) and shorter gestational age are associated with adverse early outcomes, even in infants only moderately preterm or underweight.1, 2, 3, 4 These variables are also associated with increased risk of adult-onset non-communicable diseases, suggesting that prematurity or suboptimum intrauterine growth might have pervasive effects.2, 5

Research in context

Evidence before this study

Substantial data exist describing the increased risk of neonatal infection in infants born preterm or of low birthweight, or both, especially in infants who are very preterm or of very low birthweight. But whether infection-related morbidity is increased in childhood and adolescence, especially in those born late preterm (weeksdays: 34–36+6 weeks gestational age), early term (37 weeks+0–38 weeks+6 gestational age), or with a near-normal birthweight (2500–3000 g) is unknown. We searched PubMed on Feb 1, 2016, for English-language articles with the terms “child” AND “infection” AND “hospitalisation” AND (gestational age OR birthweight OR birth length). We identified 70 articles, 30 of which we considered relevant to the hypotheses. Of these, 20 related specifically to bronchiolitis, respiratory syncytial virus, or infection of the lower respiratory tract, and two related to gastroenteritis. Findings from all studies showed that infants of low birthweight and gestational age had an increased risk of being admitted to hospital with these infections. Most remaining studies adjusted for birthweight and gestational age in analyses of other infectious exposures. Findings from only one study from 2007 reported overall infection-related admissions to hospital in childhood from population-based Danish data. The investigators of this study reported a 9% increased rate of admission to hospital for each 500 g reduction in birthweight that persisted until age 10 years. No population-based data analyse gestational age or birth length with detailed data for late preterm or early-term infants.

Added value of this study

Findings from our analysis of 30 years of total population data from Western Australia showed that reduced gestational age, birthweight, and birth length were associated with an increased risk of being admitted to hospital with an infection from birth-related hospital discharge until age 18 years. The increased risk was noted in all clinical categories of infection and for all suboptimum birth variables, including those born late preterm, early term, and with near-normal birthweight and length.

Implications of all the available evidence

A substantial and previously unrecognised proportion of children and adolescents who were born with reduced gestational age, birthweight, or birth length are at increased risk of severe infection. Further studies should investigate whether other populations have similar findings. The policy implications of these results are substantial, in terms of optimising pregnancy outcomes and preventing infection in this population. These actions would be especially relevant in resource-limited settings where suboptimum intrauterine growth and moderate prematurity are common.

Preterm birth and low birthweight are characterised by impaired immunity and heightened risk of neonatal infection.6 Postneonatal infection-related mortality is significantly increased in infants who are very preterm and of very low birthweight,1, 7 but the broader relationship between gestational age, birthweight, birth length, and infection-related morbidity in later childhood is not completely understood.8, 9 Additionally, infection risk in children born late preterm or early term, or close to optimum birthweight, is largely unknown. For this large, under-studied population, recognition of heightened infection risk would inform public health interventions.

We used 30 years of unique total population, linked health data in Western Australia to examine whether gestational age, birthweight, birth length, and ponderal index Z scores are associated with infection-related mortality, and with overall infection and infection-specific admissions to hospital throughout childhood and adolescence.

Section snippets

Study design and participants

In a population-based, data-linkage study, we identified all liveborn non-Indigenous Australian singleton births recorded in the Western Australia Birth Register (Western Australia population approximately 2·6 million) from Jan 1, 1980, to Dec 31, 2010. This method captured all births in Western Australia over this period. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked them to data about subsequent admissions to hospital or

Results

We identified 792 372 eligible births that occurred between Jan 1, 1980, and Dec 31, 2010, of which 719 311 were included in our analysis (figure 1, table 1). These individuals constituted 8 824 093 person-years of follow-up. Of 719 311 individuals, 689 714 (96%) were followed up to at least age 1 year, 579 952 (81%) to age 5 years, 466 066 (65%) to age 10 years, 373 978 (52%) to age 14 years, and 281 300 (39%) to age 18 years.

Follow-up was terminated because of death for 2950 (<1%) of 719 311

Discussion

Preterm and early term birth, low birthweight, low birth length, and low percentile birthweight and birth length Z scores were associated with a persistently increased rate of infection-related admissions to hospital in childhood. Low birthweight and birth length were more strongly associated than preterm birth with infection-related mortality. The rate of infection-related admissions to hospital was highest in those born at the earliest gestational age or with the lowest birthweight or birth

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