Fetal growth and hospitalization with asthma during early childhood: a follow-up study in Denmark

Wei Yuana,c, Olga Bassoa, Henrik T Sorensena,b and Jorn Olsena

a Danish Epidemiology Science Centre, University of Aarhus, Aarhus, Denmark.
b Department of Clinical Epidemiology, Aarhus University Hospital and Aalborg Hospital, Aarhus, Denmark.
c Shanghai Institute of Planned Parenthood Research, Shanghai, PR China.

Correspondence: Dr Wei Yuan, Danish Epidemiology Science Centre, University of Aarhus, Vennelyst Boulevard 6, DK-8000 Aarhus C, Denmark.

Abstract

Background Childhood asthma may have a fetal origin. In order to examine this hypothesis we examined the association between fetal growth indicators and hospitalization with asthma during early childhood.

Methods We performed a cohort study with 10 440 children whose mothers attended the midwife centres in Odense and Aalborg, Denmark, from April 1984 to April 1987 at approximately the 36th week of gestation. Information on hospitalization with asthma was extracted from the National Hospital Discharge Registry, which allowed a complete follow-up of all members of the cohort who remained alive and residents in the county.

Results The cumulative incidence rates of hospitalization with ‘definite’ and ‘any’ asthma were 3.5% and 5.0%, respectively, at 12 years of age. After adjusting for potential confounders, there were increased trends in the risk of asthma hospitalization with birthweight and ponderal index. More pronounced trends, particularly in the risk of definite asthma, were found among children of over the average birthweight (IRR = 1.62, 95% CI: 1.02–2.59 per 1000 g increase) or ponderal index (IRR = 1.06, 95% CI: 1.02–1.10 per 0.1 g/cm3 increase). However, the increased risk in large babies was seen only in children with a ponderal index of >=2.5 g/cm3.

Conclusion Birthweight and ponderal index were associated with childhood asthma indicated by hospitalization. Fetal growth itself, determinants of fetal growth, or any unadjusted factors that correlate with fetal growth, could cause the association.

Keywords Fetus, growth, birthweight, asthma, hospitalization, child

Accepted 20 May 2002

The prevalence of asthma and allergies is rising in many parts of the world, with large geographical variations.1,2 The World Health Organization estimates that between 100 and 150 million people suffer from asthma, which leads to over 180 000 deaths occurring annually worldwide. The causes for this rise and the variations in asthma still remain unknown. It has been suggested that the increased risk could be driven by environmental rather than genetic factors, and they could operate at any time from conception to onset of the disease. Recently some studies have suggested that prenatal factors may play a role in the aetiology.3 The evidence for the fetal origin of asthma in childhood is also strengthened by the recent finding that reduced lung function at birth is associated with recurrent wheezing in early life.4

However, data on fetal growth and the risk of asthma show conflicting results. Some studies have shown an association between increased risk of asthma and reduced fetal growth,5,6 while others found no association,7–9 or even an inverse relationship.10 Reporting bias (self- or parent-reporting) and other methodological design differences may partly explain these inconsistencies.

We used a birth cohort linked with the Danish National Hospital Discharge Registry data to examine whether fetal growth indicators were associated with the risk of hospitalization with asthma during early childhood.

Methods

Study population
The study cohort was recruited among pregnant women in Odense and Aalborg, Denmark. Both cities are served by a large public hospital, and almost all pregnant women attend antenatal care within this hospital system. From April 1984 to April 1987, 11 980 pregnant women (more than 80% of all pregnant women in the two areas) provided detailed prenatal information by means of self-administered questionnaires at approximately the 36th week of gestation. After delivery, a number of obstetric variables were extracted from the medical records, including fetal growth indicators for the offspring.11 In all, 10 440 singleton births without congenital malformations were included in the study. In order to identify these children, their personal identification numbers (CPR-number, incorporating date of birth) were extracted from the Civil Registration System by means of the mother’s CPR-number and the date of birth. This procedure provided unambiguous identification of all the children in the cohort.

Fetal growth data
Birthweight (g), birth length (cm), head circumference (cm), and placental weight (g) were recorded by midwives at delivery using standardized instruments and methods. Gestational age was calculated primarily from the last menstrual period, and it was corrected, if necessary, by ultrasound examination. The ponderal index was calculated as 100 x (birthweight (g)/birth length (cm)3). A birthweight higher than the 90th percentile of the sex-specific birthweight at each gestational week was regarded as large-for-gestational-age. The percentiles were based on the birthweight distribution between 1980 and 1992 in Denmark. Gestational weight gain was calculated by subtracting the pre-pregnancy weight from the pre-labour weight. Data on pre-labour weight were unfortunately missing for 27% of cohort members due to lack of staff, time, or opportunities to weigh the women before delivery.

We used a number of birthweight determinants, including gestational age, maternal height and pre-pregnancy weight, infant sex, and parity, to predict the expected birthweight by means of a linear regression model.12 The deviation from the expected birthweight was calculated as the observed birthweight minus the expected value.

Follow-up and hospitalization data
The birth cohort was followed to the end of 1996 by linkage with the Danish National Hospital Discharge Registry,13 which receives discharge diagnoses from all public hospitals in Denmark. This registry records up to 20 diagnoses for each hospital discharge, in accordance with the International Classification of Diseases Eighth Revision (ICD-8), which was replaced by ICD-10 on 1 January 1994. The coding is made by the doctors at the time of discharge.

We used the discharge diagnoses 493 (ICD-8) and J45–46 (ICD-10) to define ‘definite asthma’. We also defined a broader category of ‘any asthma’ which, besides the definite asthma, included possible asthma (obstructive pulmonary diseases: ICD-8 466.02, 490.01, 491.03, ICD-10 J44) because in young children asthma is difficult to diagnose. The main outcome was the first hospitalization with the above-defined discharge diagnoses, regardless of their order in the recording.

The Civil Registration System, which includes information on the vital status of all residents, was used to identify those who died or emigrated during the follow-up period (censored observations). Time at risk was calculated from birth to the first hospitalization with asthma, death, emigration, or end of study, whichever came first.

Confounding variables
The questionnaire also provided information on sociodemographic factors. These factors may confound the association between fetal growth and hospitalization with asthma by being related to fetal growth and by being alternative causes of susceptibility to asthma (or being associated with the threshold for hospitalization). The social status of the couples was divided into three levels on the basis of the family member with the highest occupational status. Maternal and paternal education was divided into three levels according to the highest school grade attained. Housing density was measured as the number of rooms per person in the dwelling. Other information included parental age, marriage status, maternal cohabitation status, parity, and number of siblings. Other potential confounders included maternal smoking and obstetric complications, such as caesarean section, vacuum extraction, induced labour, which were adjusted for in a supplementary analysis.

Statistical analysis
We measured the risk of hospitalization with asthma using the cumulative incidence rate (CIR) up to 12 years of age. The incidence rate ratio (IRR) and 95% CI were estimated using the Cox regression model.14 Fetal growth variables were categorized by using quartile boundaries if there were no existing categorizations. In the trend analysis of the risk of asthma as a function of fetal growth variables, we introduced fetal growth indicators as continuous variables into the model. Gestational age was adjusted for as a continuous variable. By examining the associations between the above potential confounders and all childhood hospitalizations, parental age, family social group, and maternal cohabitation status were identified as factors that may influence the threshold for hospitalization. The number of siblings and infant’s sex were also included in the models since they were related to hospitalization with asthma. Data analyses were done in SPSS (9.0).

Results

During the follow-up, 307 children were hospitalized with definite asthma, and 160 more with possible asthma, giving cumulative incidence rates of 3.5% for definite asthma and 5.0% for any asthma at 12 years of age. Most hospitalizations with possible asthma occurred during the first 2 years of life.

Descriptive information on the fetal growth indicators and univariate estimates of the risk of hospitalization with asthma are summarized in Table 1Go. The risk of hospitalization with asthma decreased with the length of gestation, but an increased risk was seen mainly in the small group of preterm children. There was a similar increased trend with birthweight and ponderal index, especially for the risk of definite asthma. Figures 1Go and 2Go provide in detail the relative risk of hospitalization with both definite and any asthma according to birthweight (test for trend: P = 0.07 for definite asthma) and ponderal index (test for trend: P = 0.01 for definite asthma). The trends were more pronounced among children in the higher percentiles of birthweight or ponderal index. When gestational age as well as other potential confounders were included in the analyses, there was still a higher risk of hospitalization with asthma in children large at birth (Table 2Go). Considering the more pronounced trend in the second halves of the curves in Figures 1Go and 2Go, the analyses were restricted to children above the 50th percentile of fetal growth variables (birthweight and ponderal index), and stronger associations were found (IRR = 1.62, 95% CI: 1.02–2.59 per 1000 g increase of birthweight and IRR = 1.06, 95% CI: 1.02–1.10 per 0.1 g/cm3 increase of ponderal index for definite asthma).


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Table 1 Crude incidence rate ratios (IRR) of hospitalization with asthma according to fetal growth variables: Cox regression analysis
 


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Figure 1 Crude incidence rate ratios of hospitalization with asthma according to birthweight

 

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Table 2 Adjusted incidence rate ratioa (IRR) of hospitalization with asthma according to birthweight and ponderal index: Cox regression analysis
 


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Figure 2 Crude incidence rate ratios of hospitalization with asthma according to ponderal index

 
We found no association between hospitalization with either definite or any asthma and birth length, head circumference, placental weight, and maternal gestational weight gain. Nor did we see any sex-specific difference in the above associations.

In relation to gestational age and other fetal growth determinants, birthweight was examined as weight for gestational age (small, normal, or large) and deviation from expected birthweight while adjusting for other potential confounders. Compared with children who were not ‘large-for-gestational-age’, the IRR of hospitalization with definite and any asthma among ‘large-for-gestational-age’ children were 1.67 (95% CI: 1.20–2.31) and 1.36 (95% CI: 1.02–1.81), respectively (Table 3Go). Consistent with this finding, we did not detect a trend with deviation from the expected birthweight. There was an increased risk of hospitalization for definite asthma (IRR = 1.64, 95% CI: 1.15–2.33) and for any asthma (IRR = 1.41, 95% CI: 1.04–1.91) in children with a birthweight of 600 g more than the expected value.


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Table 3 Adjusted incidence rate ratiosa (IRR) of hospitalization with asthma in large-for-gestational-age children according to ponderal index: Cox regression analysis
 
Furthermore, the increased risk in large-for-gestation children was examined according to ponderal index (Table 3Go). Compared with the children who were not ‘large-for-gestational-age’, only the children large at birth with a ponderal index >=2.5 g/cm3 had an increased risk of hospitalization with asthma, but not those with a lower ponderal index.

We also used the proportion of children hospitalized with definite asthma out of all hospitalized children as outcome measure. In this way, we reduced a possible ‘hospitalization threshold bias’ since all children had been hospitalized. A higher proportion (7.4%) of hospitalization with asthma was seen in preterm children than in full-term children (5.1%). The proportion also increased from 4.4% in children with birthweight <2500 g to 8.0% in children with birthweight >=4500 g, and from 4.6% in children with a ponderal index <2.2 g/cm3 to 6.3% in children with a ponderal index >=2.6 g/cm3.

Similar results to those presented in the tables were reproduced when additional potential confounders, e.g. maternal smoking during pregnancy and obstetric complications, were adjusted for or when the outcome was restricted to asthma diagnosed since 2 years of age and when the associations were examined during the first 6 years or the last 6 years of follow-up (data not shown).

Discussion

We found an increased risk of hospitalization with asthma in children born preterm and in children large at birth if they had a ponderal index in the high range. The traditional risk factors, such as young maternal age, low social class, and poor prenatal care,6,15,16 and the currently identified risk factors for asthma, such as maternal smoking and obstetric complications,17–19 could not explain the association.

Our study design has strengths and limitations. No selection bias is expected in this population-based design with nearly complete follow-up. Data show that birthweight and parity are usually well reported and birthweight is measured fairly accurately.20,21 Reported gestational ages are, however, often slightly longer than those estimated by means of ultrasound which may be due to a lack of compliance when reporting completed weeks of gestation rather than ongoing weeks of gestation.22 This misclassification is probably non-differential. We used hospital discharge diagnoses,13 which are not subject to information bias as self-reported data could be, but mild cases are often treated outside the hospital system and only children with severe asthma and some children with uncomplicated asthma are hospitalized. The difference in the risk of hospitalization may, however, reflect a true difference in the prevalence of the disease, a difference in the severity of the disease, a difference in diagnostic preference, or a difference in the tendency of physicians to admit patients to hospital.23 It is unlikely that differential fetal growth will influence the preference of physicians to diagnose asthma because the association between fetal growth and asthma has been inconsistent. If physicians have a tendency to lower the threshold for hospitalization for infants with reduced fetal growth, we will underestimate our findings on high birthweight. The population in Denmark has equal access to hospital services, and all hospitals of relevance for this study are public. Still, differences in the threshold of hospitalization may be associated with social factors (most likely with a lower threshold in lower social class). We attempted to reduce this potential confounding by adjusting for sociodemographic factors and by studying the proportion of hospitalization with asthma among all hospitalized children. However, residual social confounding may still result in underestimates of the risk. Still, we only included hospitalized cases (probably, more severe cases) and cannot distinguish between aetiological and prognostic factors.

The results for ‘definite asthma’ and ‘any asthma’ were virtually the same, but there were stronger associations for ‘definite asthma’. To include more possible cases of asthma that might be missed in hospital diagnoses, we also included diagnoses of obstructive pulmonary diseases in the ‘any asthma’ group. However, this broader category probably also includes respiratory infections that are inversely related to birthweight. This may explain the ‘diluted’ associations with ‘any asthma’. In order to avoid the uncertainty or the omission of asthma diagnoses in very young children, we also repeated the analyses of hospitalization with asthma since 2 or 6 years of age, and similar associations were found, albeit stronger.

Some studies,5,6 but not all, reported a higher risk of asthma or wheezing in low-birthweight children. The importance of fetal growth retardation rather than preterm delivery underlying this association was then suggested by a population-based study in Denmark.24 However, a reduced risk of reported asthma (odds ratio = 0.2; 95% CI: 0.0–0.6) was recently seen in infants with a birthweight <3.0 kg in New Zealand.10 This finding was supported by other studies reporting a decreased risk of allergic rhinitis or atopic dermatitis in low-birthweight children.25,26 Studies on the length measures, e.g. birth length and head circumference, have shown a fairly consistent association of the risk for asthma with higher birth length and head circumference.10,27 Preterm delivery has been associated with increased risk of asthma,15,16 but this higher risk in preterm children (at a given birthweight) could be interpreted as an association between enhanced fetal growth and asthma, and the element of preterm birth may have relatively little importance.

The size of a fetus at any stage of pregnancy reflects a complex interaction between the time since fertilization, the rate of fetal cell multiplication, and cell growth.28 We expect that promoting factors which operate late in pregnancy, in contrast with inhibiting factors,28 will cause asymmetric, but enhanced, fetal growth. Therefore, our study further related asymmetric enhanced fetal growth to the risk of hospitalization with asthma since the increased risk was only seen in large babies with a high ponderal index.

The biological mechanisms for this association are unknown. Many prenatal factors are known to determine fetal growth patterns, and these patterns are also, to some extent, indicators of some other exposures in later life. The pronounced and consistently increased trend in the prevalence of asthma in children (but not in adults) may reflect the role of some ‘new’ risk factors in early life rather than in adult life. The associations could of course also be secondary to lower fertility and better socioeconomic status leading to a higher birthweight and reduced exposure to infectious agents in early childhood.

Infants who develop allergy already have an altered immune response at birth.3 Among prenatal allergen exposures, maternal diet and nutrition, which include a great number of food antigens, are very important determinants of fetal growth. Studies have indicated that avoidance of common dietary allergens (milk and dairy products, eggs, fish and peanuts) during pregnancy reduces the risk and the severity of atopic eczema.29 Therefore intake of these nutrients, which benefit fetal growth, may increase the risk of atopic diseases. On the other hand, the enhanced fetal growth with a higher rate of cell proliferation and/or a large number of precursor cells exposed to early antigens may in itself contribute to the higher risk of asthma in childhood since atopy has been linked with an imbalance in thymus-derived lymphocytes,30 and a similar association between fetal growth and leukaemia has previously been found.31 Our findings also suggested the importance of enhanced fetal growth in the late stage of gestation, which to some extent is in line with the observation that the positive response of fetal T cells was seen from 22 weeks gestation.3 A recent study4 found an association, independent of maternal smoking during pregnancy, between obstructive airway disease in early life and the infant’s airway structural alteration measured by reduced lung function at birth. This may suggest a possible pathway as relative structural insufficiency of the fetal airway development in enhanced fetal growth. Another possible mechanism for the observed association may be that fewer serious infections in large newborns during early childhood could be responsible for the higher risk of asthma.32

In conclusion, the risk of hospitalization with asthma during early childhood was associated with asymmetrical enhanced fetal growth, characterized by a high ponderal index in large newborns. Our data do not allow us to establish whether enhanced fetal growth is a cause of this association or just an indicator of some other factors acting on fetal growth in the late stage of gestation.


KEY MESSAGES

  • Anthropometric measures at birth and hospitalization data were used to investigate the association between fetal growth and childhood asthma.
  • The risk of hospitalization with asthma during childhood increased with birthweight and ponderal index.
  • The increased risk of asthma in large babies was more pronounced in children with a high ponderal index.
  • It is unknown whether enhanced fetal growth is a cause of the association or just an indicator of other in utero factors underlying the association.

 

Acknowledgments

The activities of The Danish Epidemiology Science Centre are financed by a grant from The Danish National Research Foundation.

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