Low birth weight and respiratory disease in adulthood: a population-based case-control study.
ABSTRACT The proportion of low and very low birth weight births is increasing. Infants and children with a history of low and very low birth weight have an increased risk of respiratory illnesses, but it is unknown if clinically significant disease persists into adulthood.
To determine if a history of low birth weight is associated with hospitalization for respiratory illness in adulthood.
This study was a population-based, case-control study. Cases were adults 18 to 27 years of age who were hospitalized for a respiratory illness from 1998 to 2007 within Washington State who could be linked to a Washington State birth certificate for the years 1980 to 1988. Four control subjects, frequency matched by birth year, were randomly selected from Washington State birth certificates for each case patient. Control subjects who died before age 18 were excluded.
Two levels of exposure were identified: (1) very low birth weight (birth weight <1,500 g) and (2) moderately low birth weight (birth weight, 1,500-2,499 g). Normal birth weight individuals (2,500-4,000 g) were considered unexposed. Respiratory hospitalizations were defined using discharge diagnosis codes. Logistic regression was used to calculate the odds ratio for hospitalization comparing exposed and unexposed individuals. A total of 4,674 case patients and 18,445 control subjects were identified. The odds ratio for hospitalization for respiratory illness was 1.83 for very low birth weight (95% confidence interval, 1.28-2.62; P = 0.001) and 1.34 for moderately low birth weight (95% confidence interval, 1.17-1.53; P < 0.0005). This association remained after adjustment for birth year, sex, maternal age, race, residence, and marital status.
Adults with a history of very low birth weight or moderately low birth weight were at increased risk of hospitalization for respiratory illness.
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ABSTRACT: To assess whether lung function in late childhood had improved in subjects born extremely prematurely in the early 1990s compared to the early 1980s, and whether neonatal factors in the respective periods had different impact on long-term pulmonary outcome. Population-based, controlled cohort study. Lung function was determined in 81 of 86 (94%) eligible subjects born with gestational age < or =28 weeks or birthweight < or =1000 g in Western Norway in 1982-85 (n=46) and 1991-92 (n=35), and in 81 matched control subjects born at term. The incidence of bronchopulmonary dysplasia was similar in the two periods. At follow-up, airway obstruction, hyper-responsiveness and pulmonary hyperinflation were similarly increased in both preterm cohorts compared to matched controls. Furthermore, current lung function was similarly related to neonatal respiratory disease in both birth-cohorts: FEV1 was reduced with respectively 18.6% and 18.7% of predicted in preterms dependent on supplemental oxygen at 36 weeks postmenstrual age. Lack of antenatal treatment with corticosteroids and prolonged neonatal oxygen treatment predicted similar significant airway obstruction in the two birth-cohorts. Preterms born in different eras of neonatology had similar long-term decreases in lung function. Long periods of oxygen supplementation are still required to salvage immature infants, and airway obstruction may still be a common long-term outcome.Acta Paediatrica 06/2006; 95(5):547-54. · 1.97 Impact Factor
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ABSTRACT: To determine the relationship between lung function at 11 years of age and bronchopulmonary dysplasia (BPD) in very low birthweight (VLBW) children. This study comprised 154 consecutive surviving VLBW children, divided into three groups with respect to their neonatal respiratory morbidity: group I developed BPD; group II required assisted ventilation but did not develop BPD; and group III required no assisted ventilation. Lung function tests were measured on 120/154 (77.9%) children at 11 years of age. The relationship between various lung function variables and neonatal lung disease was analysed by multiple linear regression. Several lung function variables reflecting airflow were significantly diminished in the BPD group (n = 15), and residual volume was significantly higher. Despite poorer lung function overall, few children in the BPD group had lung function abnormalities in the clinically significant range (n = 2[13.3%] with a forced expired volume in 1 $ < 75% predicted; n = 2[13.3%] with a forced vital capacity < 75% predicted; n = 1 [6.7%] with a residual volume/total lung capacity > 35%). There were no significant differences in lung function variables between group II (n = 41) and group III (n = 64). Changes in lung function tests between 8 and 11 years did not very significantly between the three groups. VLBW children with BPD in the newborn period have period have poorer lung function at 11 years of age than other surviving VLBW children without BPD, although few have lung function abnormalities in the clinically significant range.Journal of Paediatrics and Child Health 08/1996; 32(4):339-43. · 1.25 Impact Factor
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ABSTRACT: Advances in perinatal care have increased the number of premature babies who survive. There are concerns, however, about the ability of these children to cope with the demands of adulthood. We linked compulsory national registries in Norway to identify children of different gestational-age categories who were born between 1967 and 1983 and to follow them through 2003 in order to document medical disabilities and outcomes reflecting social performance. The study included 903,402 infants who were born alive and without congenital anomalies (1822 born at 23 to 27 weeks of gestation, 2805 at 28 to 30 weeks, 7424 at 31 to 33 weeks, 32,945 at 34 to 36 weeks, and 858,406 at 37 weeks or later). The proportions of infants who survived and were followed to adult life were 17.8%, 57.3%, 85.7%, 94.6%, and 96.5%, respectively. Among the survivors, the prevalence of having cerebral palsy was 0.1% for those born at term versus 9.1% for those born at 23 to 27 weeks of gestation (relative risk for birth at 23 to 27 weeks of gestation, 78.9; 95% confidence interval [CI], 56.5 to 110.0); the prevalence of having mental retardation, 0.4% versus 4.4% (relative risk, 10.3; 95% CI, 6.2 to 17.2); and the prevalence of receiving a disability pension, 1.7% versus 10.6% (relative risk, 7.5; 95% CI, 5.5 to 10.0). Among those who did not have medical disabilities, the gestational age at birth was associated with the education level attained, income, receipt of Social Security benefits, and the establishment of a family, but not with rates of unemployment or criminal activity. In this cohort of people in Norway who were born between 1967 and 1983, the risks of medical and social disabilities in adulthood increased with decreasing gestational age at birth.New England Journal of Medicine 07/2008; 359(3):262-73. · 51.66 Impact Factor
Low birthweight and respiratory disease in adulthood: A population-based case-
1-3Eric C. Walter, MD; 1,2William J. Ehlenbach, MD; 1,2David L. Hotchkin, MD, 1,3Jason
W. Chien, MD; 2Thomas D. Koepsell, MD
1Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle
WA; 2Department of Epidemiology, University of Washington, Seattle, WA; 3Clinical
Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Request for reprints should be addressed to:
Eric C Walter, MD
Fred Hutchinson Cancer Research Center
1100 Fairview Ave N
PO Box 19024
Seattle, WA 98109-1024
Eric C Walter, MD
Fax 206 667 5765
Phone 206 450 3727
Sources of support: Drs. Walter, Ehlenbach, and Hotchkin were supported by a National
Institutes of Health training grant (T32 HL 007287).
The funding source had no role in the study design, collection, analysis, and
interpretation of the data, writing of the report, or in the decision to submit the report for
Running title: Birthweight and respiratory disease
Subject code: 95; Neonatal lung disease
Word Count: 2660
At a glance commentary:
Page 1 of 36
AJRCCM Articles in Press. Published on April 16, 2009 as doi:10.1164/rccm.200901-0046OC
Copyright (C) 2009 by the American Thoracic Society.
Scientific Knowledge on the Subject: Infants and children with a history of low
birthweight are at increased risk of respiratory illness. Long term follow-up studies in
adolescents and young adults with a history of low birthweight have reported decreased
pulmonary function testing and increased respiratory symptoms compared to those with a
history of normal birthweight. However, it is unknown if low birthweight is associated
with clinically significant respiratory disease in adulthood.
What This Study Adds to the Field: We report an increased risk of hospitalization for
respiratory disease among adults with a history of low birthweight compared to adults
with a history of normal birthweight. As birthweight decreased, the risk of adult
Online Data Supplement: This article has an online data supplement, which is
accessible from the issue’s table of content online at www.atsjournals.org.
Page 2 of 36
Rationale: The proportion of low and very low birthweight births is increasing. Infants
and children with a history of low and very low birthweight have an increased risk of
respiratory illnesses but it is unknown if clinically significant disease persists into
Objective: To determine if a history of low birthweight is associated with hospitalization
for respiratory illness in adulthood.
Methods: A population-based case-control study: Cases were adults ages 18-27
hospitalized for a respiratory illness from 1998-2007 within Washington State who could
be linked to a Washington State birth certificate for the years 1980-1988. Four controls,
frequency matched by birth year, were randomly selected from Washington State birth
certificates for each case patient. Controls that died prior to age 18 were excluded.
Measurements: Two levels of exposure were identified: very low birthweight
(birthweight <1500 grams) and moderately low birthweight (birthweight 1500-2499
grams). Normal birthweight individuals (2500-4000 grams) were considered unexposed.
Respiratory hospitalizations were defined using discharge diagnosis codes. Logistic
regression was used to calculate the odds ratio for hospitalization comparing exposed and
Main Results: 4674 case patients and 18,445 controls were identified. The odds ratio for
hospitalization for respiratory illness was 1.83 for very low birthweight (95% CI 1.28-
2.62, p=0.001) and 1.34 for moderately low birthweight (95% CI 1.17-1.53, p<0.0005).
This association remained after adjustment for birth year, sex, maternal age, race,
residence and marital status.
Page 3 of 36
Conclusions: Adults with a history of very low birthweight or moderately low
birthweight were at increased risk of hospitalization for respiratory illness.
Abstract Word Count: 250
Key Words: Infant, Low Birth Weight; Infant, Very Low Birth Weight; Respiratory
Tract Diseases; Adult; Survivors
Page 4 of 36
Since the mid 1980s the proportion of low birthweight (LBW) and very low birthweight
(VLBW) births have increased over 20% in the United States. In 2005, there were over
330,000 LBW and 60,000 VLBW births in the US (approximately 8.2% and 1.5% of all
births, respectively) (1). With improved neonatal care, survival of infants with below
normal birthweight has improved (2, 3) and many are now surviving into adulthood (4-6).
Survival to adulthood was approximately 65% for infants born less than 32 weeks
gestational age in a recent longitudinal study from Norway (5). In the US this would
represent more than 200,000 new adult survivors each year. The increased prevalence of
LBW and improved survival has led to an increase in the incidence of chronic illnesses
associated with LBW (3, 7-9). Bronchopulmonary dysplasia (BPD) is a chronic lung
disease associated with prematurity. BPD is defined as oxygen dependence for at least
28 postnatal days for infants ≥32 weeks postmenstrual age, or oxygen dependence at 36
weeks postmenstrual age for infants born <32 weeks (10). The increasing incidence of
extreme prematurity and improved survival has led to an increase in BPD (3, 6, 9, 10), a
3-fold increase in one study (3).
Survivors of VLBW, both with and without a history of BPD, have been found to have
abnormal pulmonary function testing as infants (11-13), children (14, 15), and
adolescents (16-19). Less is known about the effects of LBW on adult respiratory
disease. We therefore sought to determine if adults with a history of VLBW were at
increased risk of hospitalization for respiratory illness using a population-based case-
control design. We also sought to see if an association was present for specific
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respiratory diagnoses including asthma, respiratory infection, and acute respiratory
failure. Additionally we evaluated the exposure of moderately low birthweight (MLBW,
birthweight 1500 to 2499 grams) to see if a similar association existed for this
intermediate exposure category. Some of the results of these studies have been
previously reported in the form of an abstract (20).
We conducted a population based case-control study. Potential cases were identified
from the Washington (WA) State Comprehensive Hospital Abstract Reporting System
(CHARS) discharge database, and defined as individuals hospitalized from January 1,
1998 to December 31, 2007, who were 18 years or older at the time of hospitalization,
and who received a discharge diagnosis of a respiratory illness. Respiratory illnesses
were defined using specific International Classification of Diseases, Ninth Revision
(ICD-9) diagnosis and procedure codes representing acute and chronic respiratory
disease, respiratory infections, respiratory symptoms, and non-operative mechanical
ventilation (Online supplement Table E1). Selection was limited to those individuals
with a respiratory diagnosis code present among the first four listed discharge diagnoses.
Individuals thus identified from CHARS were retained as cases if they could be linked to
a birth certificate in the WA State Birth Certificate database for the years 1980 to 1988.
Linkage was performed using date of birth and the first two letters of the first and last
Page 6 of 36
name. Potential cases that matched to two or more different birth certificates were
Controls were randomly selected from the WA State birth certificate database (excluding
cases), and frequency matched to cases by birth year. Four times as many controls as
cases were selected. Controls were filtered through the WA State Department of Health
death file to exclude individuals who were known to have died prior to the age of 18.
This study was approved by the Institutional Review Board at the University of
Outcomes and exposure
The primary outcome was hospitalization for respiratory disease between the ages of 18
to 27. The primary exposure was LBW. LBW was classified as: VLBW (birthweight <
1500 grams) and MLBW (birthweight 1500 to 2499 grams). Normal birthweight (NBW,
birthweight 2500 to 4000 grams) individuals were considered unexposed. Individuals
with macrosomia (birthweight > 4000 grams) were excluded. Exploratory analyses were
performed for 3 a priori identified subgroups of respiratory illness hospitalizations:
asthma, respiratory infection, and respiratory failure requiring mechanical ventilation.
Subgroups were defined using ICD-9 discharge codes and are described in the online data
supplement (Table E2).
Page 7 of 36
Clinical variables potentially associated with birthweight and subsequent respiratory
illnesses were identified from birth certificate data. They included birth year, sex,
maternal age, and maternal race/ethnicity. Birth year was modeled continuously and
maternal age categorically. Additional variables included maternal smoking status,
maternal marital status, induction of labor, delivery type, and maternal residence.
Clinical variables are further described in the online data supplement.
All statistical analyses were performed using STATA 10.0 (StataCorp, College Station,
TX). Crude odds ratios (OR) comparing risk of hospitalization in subjects with a history
of VLBW or MLBW to subjects with a history of NBW were calculated using logistic
regression with robust standard errors. Variables with a 2-sided P value of <0.1 in
univariate analyses were included in multivariable analyses. In addition, as cases and
controls were frequency-matched on birth year, this was included in multivariable
analyses. Mantel-Haenszel stratified analyses and logistic regression were used to
evaluate for confounding and effect modification by covariates. The likelihood ratio test
was used to assess for interactions between birthweight and maternal smoking status and
birthweight and birth year. A 2-sided P value of <0.05 was considered statistically
Page 8 of 36
From 1980 to 1988 there were 628,508 live births (mean 69,834 births/yr) in WA State
(21). From 1998 to 2007, 11,437 patients were identified through CHARS as having
been hospitalized for a respiratory illness between the ages of 18 to 27. Of these patients,
5777 were born in WA as determined by linkage to the Birth Certificate database. After
excluding duplicate linkages (n=358, 6.2%) 5419 cases were identified. Cases were
excluded for macrosomia (n=730, 13.5%) missing birthweight (n=14, 0.3%), and
implausible birthweight [BW=113 grams, (n=1)]. 21,659 controls were randomly
selected. Controls were excluded for macrosomia (n=3120, 14.4%) and missing
birthweight (n=94, 0.4%). Maternal and delivery characteristics of cases (n=4674) and
controls (n=18,445) are described in Table 1. Cases were more likely to be female, have
mothers who were younger, African American, unmarried, and smoked during
pregnancy. Hyaline membrane disease was more likely among cases (p=0.005 when
missing data included, p=0.002 when excluded). Patients missing data at one or more
covariates of interest were excluded in subsequent analyses [n=517 (2.2%) for entire
cohort; n=796 (8.4%) for 1984 to 1988 analyses].
Individuals with a history of VLBW or MLBW were more likely to be hospitalized for a
respiratory illness as young adults [VLBW OR 1.83, (95% CI 1.28 to 2.62), p=0.001;
MLBW OR 1.34, (95% CI 1.17 to 1.53), p<0.0005). The trend of an increased risk of
hospitalization as birthweight decreased was statistically significant (p<0.0005). After
adjustment the odds of hospitalization were largely unchanged [VLBW OR 1.68 (1.16 to
2.42), p=0.006; MLBW OR 1.26 (1.10 to 1.44); p=0.001; p<0.0005 for trend] (Table 2).
Page 9 of 36
Recording of maternal smoking status on birth certificates began in 1984. Limiting the
analysis to those born after 1983 decreased the number of cases and controls by 60% to
1852 and 7331, respectively. Maternal smoking during pregnancy was associated with an
increased risk of her child being hospitalized for respiratory disease as an adult [OR 1.56
(1.39 to 1.74), p<0.0005]. There was no evidence of effect modification by smoking as
determined by the Breslow-Day test of homogeneity (p=0.25). Using the subset of
patients from 1984 to 1988 and including the same covariates as for the full sample, the
adjusted OR for hospitalization for a respiratory illness was 1.30 and 1.33 for VLBW and
MLBW survivors respectively. After further controlling for maternal smoking, the
adjusted ORs were 1.29 and 1.27, respectively (Table 3). The linear trend test for LBW
remained significant in both analyses (p=0.010 and p=0.027, respectively).
In unadjusted subgroup analyses a history of VLBW or MLBW was associated with
hospitalization for asthma, respiratory infections, and respiratory failure requiring
mechanical ventilation (Table 4). Specifically, individuals with a history of MLBW had
a 39% increased odds of hospitalization for asthma. The odds in those with a history of
VLBW were increased 2-fold. In MLBW survivors the ORs for respiratory infection and
respiratory failure were both 1.5-fold higher. For VLBW survivors the odds of
respiratory infection were increased 2-fold and the odds of respiratory failure requiring
mechanical ventilation were increased 2.6-fold. After adjustment ORs were attenuated
slightly but remained significant for all analyses except for respiratory infections in
Page 10 of 36
VLBW survivors (p=0.059). The linear trend of an increased risk of hospitalization as
birthweight decreased remained significant for all adjusted and unadjusted subgroup
To further adjust for maternal smoking in each subgroup the cohort was again limited to
births from 1984 to 1988. A trend of an increased risk of hospitalization as birthweight
decreased was again seen for respiratory infections [OR 1.57 (95% CI 1.18 to 2.09),
p=0.002] and respiratory failure [OR 1.86 (95% CI 1.30 to 2.65), p=0.001]. There was
no longer a significant trend between the odds of hospitalization for asthma and
birthweight category [OR 1.02 (95% CI 0.77 to 1.36), p=0.877) (See Table E5 in the
online data supplement).
We report the largest population based study to date of respiratory illness in adults with a
history of LBW. VLBW survivors had 83% higher odds of hospitalization for respiratory
illnesses as young adults when compared to NBW individuals. For MLBW survivors the
odds were 34% higher. This risk remained present after adjusting for maternal
sociodemographic characteristics including age, race, marital status and urban/rural
residence, and infant factors including sex and birth year. VLBW survivors were at
greater risk for hospitalization for respiratory disease than MLBW survivors. This
graded risk, with infants of lower birthweight at greater risk of later lung disease, is
biologically plausible. Infants with a lower birthweight are more likely to be born at an
Page 11 of 36
earlier gestational age and are known to be at higher risk of lung injury and BPD (9, 10,
22-24). We were unable to determine if gestational age modified the effect of
birthweight on adult hospitalizations as has been hypothesized (25). Gestational age
according to last menstrual period was available in our data, but was not felt to be
accurate. Others have reported the inaccuracies in estimation of gestational age
estimation using the last menstrual period as well (26-28). An increased risk of
hospitalization was present across all three subgroups of respiratory illness: asthma,
respiratory infections, and respiratory failure. While the number of events was low,
LBW survivors were at a particularly high risk of the most severe condition, respiratory
failure requiring mechanical ventilation.
Maternal smoking may explain a small amount of the association between birthweight
and risk of hospitalization. Adjustment for smoking status attenuated the OR for MLBW
from 1.33 to 1.27 and for VLBW from 1.30 to 1.29 (Table 3). However, birthweight
remained significantly associated with adult hospitalizations after adjustment for
maternal smoking in MLBW survivors. The trend also remained significant.
The increased risk of hospitalization may be explained by poor lung development among
LBW infants. Poor lung function in healthy term infants is associated with decreased
lung function in young adults (29). It is reasonable to assume this relationship would also
be true for LBW survivors. Although we were unable to assess for a history of BPD,
some LBW survivors in our study would have been at risk for “old” BPD. Old BPD is
characterized by diffuse alveolar damage and neutrophilic inflammation leading to
Page 12 of 36
fibrosis (6, 9). Abnormal pulmonary anatomy has been seen on computed tomography
scans in adult survivors of moderate to severe BPD (30). The sequelae of lung injury
may alter respiratory anatomy and physiology for years to come. This may predispose
survivors to air trapping, poor airway clearance, or gas exchange disorders. LBW
survivors may also be more likely to have upper airway problems such as tracheal
stenosis, tracheomalacia, or vocal cord paralysis placing them at higher risk of respiratory
illness. Additionally, LBW, in the absence of BPD, may confer an increased risk of adult
respiratory disease as hyaline membrane disease, which is associated with old BPD, was
relatively uncommon in our study.
Young adult survivors of BPD have been reported to have abnormal pulmonary function.
In 1990, Northway et al. reported mild airflow obstruction, airway hyper-responsiveness,
and air trapping in 26 young adult survivors (31). Others have reported mild airflow
obstruction in extremely LBW (16) and VLBW survivors (17). Low normal range
exercise capacity has been reported in LBW survivors (32). Others have not found
significant differences in pulmonary function between LBW survivors and NBW
controls. Narang et al. recently reported that mean z-scores for FEV1 and forced vital
capacity were slightly below normal among LBW survivors and NBW controls, but there
were no significant differences between the two groups (25). In addition to abnormal
PFTs, LBW survivors have reported a greater prevalence of respiratory symptoms and
doctor-diagnosed asthma compared to NBW survivors (16, 19, 25).
Page 13 of 36
Our data should be interpreted with some caution. We were unable to assess for
differential migration out of WA in our control group. It is possible that NBW infants
were more likely to move out of the state than LBW infants. If these controls had been
hospitalized as young adults in other states we would have missed these hospitalizations.
However, we estimate that 14% of NBW controls would need to have been hospitalized
outside of WA to eliminate the observed excess in respiratory disease hospitalizations for
VLBW survivors. This seems unlikely because only about 0.3% of young adults are
hospitalized for diseases of the respiratory system in any given year (33). The use of
linked databases has limitations. However, it seems unlikely that birthweight would have
been recorded any differently for cases and controls, and any misclassification would
tend to bias our estimates towards the null.
We were only able to assess maternal socio-economic status indirectly. Nevertheless,
after adjustment for maternal age and sociodemographic characteristics results were
largely unaffected. We were also unable to assess for smoking exposure in adult
survivors. If LBW survivors had smoked more than NBW survivors they may have been
at increased risk of respiratory disease. However, it is unknown if differences in smoking
behavior exist between these two groups. Smoking has been reported to be more
prevalent among LBW survivors compared to NBW survivors, although lung function
did not differ between the groups (25). Others have not found differences in smoking
behavior between the two groups (8). Finally, similar to all long term follow-up studies,
we identified a study population born in an era prior to the routine use of antenatal
corticosteroids and surfactant therapy. These practices have decreased the incidence of
Page 14 of 36
old BPD. The incidence of “new” BPD, however, is increasing. New BPD is primarily a
result of immature lung development and is associated with fewer, larger alveoli and
disrupted capillary development. It is unknown if these survivors will have the same risk
of adult respiratory illness as our study population.
We report a previously unrecognized excess risk of hospitalization for respiratory illness
in young adults with a history of LBW. Our findings suggest that not only are VLBW
and MLBW survivors at increased risk of long term respiratory disorders but that these
disorders are clinically significant and associated with increased health care utilization.
In our study the population attributable risk percent, the percentage of disease in a
population attributable to a particular exposure, was estimated to be 1.8%. If this were
extrapolated to the 1.2 million U.S. hospitalizations for respiratory illnesses per year for
ages 18-44, low birthweight may account for over 21,000 adult hospitalizations per year,
with charges in excess of $225 million per year (33-35). The number of excess
hospitalizations may grow in view of the improving survival and increasing prevalence of
BPD. If confirmed, these findings suggest that internists, and not just pediatricians, need
to be aware of their patient’s birth history. Future studies should focus on identifying
other risk factors that may modify this risk so that interventions can be designed to
improve outcomes and reduce healthcare utilization costs.
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