A retrospective study of the relationship between childhood

asthma and respiratory infection during gestation

C. H. HUGHES, R. C. M. JONES*, D. E. WRIGHT² and F. F. DOBBS³

Estover Health Centre, *Roborough Surgery, ²School of Mathematics and Statistics, University of Plymouth and

³Department of General Practice and Primary Care, University of Plymouth, Plymouth, UK

Summary

Background Wheeze in children has been found to be associated with prior antepartum

haemorrhage and raised levels of IgE in cord blood, and acute wheezing episodes are

intimately linked with respiratory viral infections.

Objective To assess the relationship between maternal presentation with respiratory tract

infections in pregnancy and childhood asthma, taking into account factors which could

affect presentation.

Methods This was a case-control study of 200 asthmatic children, 5±16-year-old, age-

matched with one control, having no recorded history of wheeze. Data on respiratory tract

infections, maternal wheeze, atopy and smoking was collected from primary care records.

Deprivation score was assessed according to small residential areas and subjects were

equally distributed between four general practices in Plymouth, UK.

Results Presentation with respiratory tract infections during pregnancy was signi®cantly

associated with childhood asthma (OR 1.69, 95% con®dence interval 1.05±2.77, P� 0.03).

The association was marginally stronger for infections in the ®rst trimester (OR 2.30, 95%

CI 1.05±5.41, P� 0.04) and for those with cough during pregnancy (OR 2.24, 95% CI

1.23±4.22, P� 0.007). The associations remained signi®cant after allowing for the effect of

the independent variables (gender, maternal smoking, maternal wheeze, allergic rhinitis,

eczema, asthma treatment in pregnancy and deprivation [Townsend] score), using multiple

logistic regression analysis (ORs and 95% CIs 1.91, 1.14±3.22; 2.32, 1.01±5.34 and 2.29,

1.17±4.48, respectively). There was also an association between numbers of presentations

with respiratory infections and childhood asthma (test for trend, P� 0.02).

Conclusions This study has shown an association between presentation with respiratory

infection during gestation and childhood asthma. The results were not affected by the other

independent variable factors studied and therefore provide some evidence to support the

theory that respiratory viruses may be implicated in the aetiology of asthma.

Keywords: asthma, children, pregnancy, viral infection

Clinical and Experimental Allergy, Vol. 29, pp. 1378±1381. Submitted 7 September 1998;

revised 23 October 1998; accepted 29 March 1999.

Introduction

The mechanisms underlying the rise in incidence of asthma

in recent decades are largely unknown. The discovery that

hay fever and eczema had an inverse relationship with birth

order [1] led to the theory that viral infection in childhood

might prevent the development of atopy. The ®nding of an

inverse association between skin sensitization and high

speci®c immunoglobulin (Ig)E levels in young adults and

the presence of hepatitis A antibodies [2] appeared to lend

support to this theory. There was a similar relationship

with allergic rhinitis but not in the small number (3.6%)

with asthma, in those sensitized to airborne allergens.

Only in the hepatitis A seronegative group was there a

clear inverse relationship between birth order and high

speci®c IgE level. This could be explained if predominantly

Clinical and Experimental Allergy, 1999, Volume 29, pages 1378±1381

1378 q 1999 Blackwell Science Ltd

Correspondence: C. H. Hughes, Estover Health Centre, Leypark Walk,

Estover, Plymouth PL6 8UE, UK.

respiratory viral infections, transmitted from older to

younger siblings, had a protective effect. Conversely, it

could indicate a causative effect, if a higher incidence of

these infections resulted from greater social contact by

parents early in their reproductive careers, the infections

then being transmitted to their children. This is a distinct

possibility, since mothers having fewer children are more

likely to work, particularly in pregnancy [3], which would

tend to result in greater social contact.

Respiratory viruses are intimately linked with wheezing

episodes [4] and respiratory viral infection in early life has

been associated with subsequent wheeze and bronchial

lability [5]. Antepartum haemorrhage [6] and raised levels

of IgE in cord blood [7] are associated with wheeze in

children, although a more sensitive indicator of future atopic

eczema [8] and atopy including asthma [9] may be a

reduced level of interferon gamma produced by antigen

stimulated cord blood mononuclear cells (CBMCs). It is

also known that maternal exposure to pollen in pregnancy

induces a foetal response in the form of an increase in the

pollen-stimulated proliferative response of infant CBMCs

[10].

We sought to test the hypothesis that respiratory viral

infection might be implicated in the aetiology of asthma,

possibly through an adverse effect on the foetal immune

system.

This study aimed to assess the relationship between

presentation with maternal respiratory infections during

gestation and childhood asthma, taking into account certain

factors which would affect presentation.

Methods

A case-control study was designed to compare rates of

maternal presentation with respiratory infection during

gestation between children diagnosed in primary or second-

ary care as having asthma and age-matched controls, having

no recorded history of wheeze. All data, except deprivation

(Townsend) scores, were taken from primary care records.

A sample size calculation indicated that 195 in each group

would have an 80% power of detecting an OR of 2.0, using

a two-tailed test of signi®cance at the 5% level. Fifty

asthmatics, aged 5±16 years, treated in the year to July

1997 and 50 controls, were randomly selected from each

of four general practices. Seven asthmatics and ®ve

controls were excluded, whose mothers were not registered

in the same practice and replacements selected. Those

extracting data were blind to the status of the mothers

with respect to their case or control grouping. Respiratory

tract infections (RTI) in pregnancy were recorded as written

in the notes. They were placed in two main categories:

(a) colds and upper respiratory tract infection (URTI), and

(b) cough wherever this had been speci®ed, and under the

following subheadings if described alone: sinusitis, otitis

media, laryngitis, sore throat or tonsillitis, `¯u and pneu-

monia, with the trimester in which the illness commenced.

Wheeze, alone, was not recorded as RTI and care was

taken to avoid recording more than one consultation for

the same episode of illness. The following were also

recorded: gender, lifetime prevalence of atopy in the child-

ren, maternal allergic rhinitis, eczema or dermatitis, wheeze,

history of maternal smoking or non-smoking; speci®c

treatment for asthma during the pregnancy, presentation

with illness in pregnancy other than RTI, and Townsend

score of each subject's current enumeration district. The

Townsend score is recognized as a sensitive measure of

deprivation and includes four variables: unemployment,

overcrowding, lack of owner-occupied housing and of car

ownership. Data was analysed using the S-Plus package.

Results

Total numbers of asthmatics, treated in the year to July

1997, constituted 11.8% of all 5±16-year-old children in

the four practices. Median ages of asthmatic and control

children were 10.87 and 10.89 years, respectively. Details

of the study are shown in the tables. Numbers presenting

with sinusitis, otitis media, laryngitis and sore throats

were small and were included under RTI. Two cases of

`¯u were included under RTI and cough. Mothers of asth-

matics were signi®cantly more likely to present with RTI

than mothers of controls, during pregnancy (OR 1.69,

P� 0.03), in the ®rst trimester (OR 2.30, P� 0.04), and

with cough (OR 2.24, P� 0.007) (see Table 1). Independent

variable factors studied were: RTI in pregnancy, gender,

maternal allergic rhinitis, dermatitis or eczema, wheeze,

history of smoking, asthma treatment in pregnancy and

Townsend score. After allowing for the effect of these

factors, using multiple logistic regression analysis, the

associations between RTI in pregnancy and the dependent

variable, childhood asthma, remained signi®cant (see

Table 2). Data on smoking in pregnancy was available

for 47% of the asthmatic and 42% of the control group.

When this was substituted in the model for overall history

of smoking, producing a loss of statistical power, the

adjusted OR for RTI during pregnancy was 1.74 (0.79±

3.83) and for RTI in the ®rst trimester, 5.07 (1.02±25.14). A

dose-dependent relationship was found between number

of presentations with RTI in pregnancy and asthma in

children, using the Wilcoxon signed rank test for paired

data, P� 0.02.

Discussion

This study has shown an association between presen-

tation with respiratory tract infections during gestation,

Respiratory infection during gestation 1379

q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, 1378±1381

particularly those associated with cough, and childhood

asthma and that the risk was greatest in the ®rst trimester.

The associations remained after adjustment for gender,

maternal allergic rhinitis, eczema or dermatitis, wheeze,

smoking, treatment for asthma in pregnancy and deprivation

score. A dose-dependent effect was also found. Mothers

of asthmatic children were more likely to have a history

of wheeze, although not signi®cantly so, possibly as a

consequence of dilution of the control group with children

with unrecorded wheezing episodes. The overall prevalence

of maternal wheeze in this study was comparable with

that found in early adult life in 1974 in the UK [6]. Figures

for maternal smoking in the two groups were similar. After

adjustment for the limited data on smoking in pregnancy,

RTI in the ®rst trimester was still signi®cantly different,

but with wide con®dence limits. Inclusion of Townsend

scores in the logistic regression will have taken into account

social factors which could in¯uence maternal presenta-

tion rates. In addition, numbers presenting with illnesses

in pregnancy other than RTI were virtually identical, sug-

gesting a lack of bias with respect to tendency to present.

We may assume that the majority of respiratory illnesses

would have been associated with viral infection and that

numbers presenting probably represent only a small propor-

tion of the actual incidence of infections.

This study gives an indication of an excess of respiratory

1380 C. H. Hughes et al.

q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, 1378±1381

A C OR (95% CI) Adjusted OR (95% CI)

RTI in pregnancy 60 40 1.69 (1.05±2.77)* 1.91 (1.14±3.22)

Sex

Male 100 84 1.50 (0.94±2.42) 1.25 (0.81±1.92)

Female 100 116

Maternal

Wheeze 62 44 1.50 (0.95±2.39) 1.23 (0.72±2.11)

Hay fever 33 24 1.39 (0.79±2.49) 1.30 (0.66±2.56)

Other allergic rhinitis 16 20 0.78 (0.36±1.66) 0.44 (0.20±0.98)

Eczema/dermatitis 74 69 1.07 (0.69±1.66) 1.06 (0.68±1.67)

Asthma Rx in pregnancy 12 4 3.00 (0.91±12.76) 2.03 (0.58±7.18)

Smokers² 103 95 1.17 (0.76±1.82) 1.05 (0.67±1.64)

Non-smokers² 82 88

Townsend score 1.34 1.26 1.03 (0.97±1.09)§ 1.05 (0.98±1.12)

A� asthmatics, C� controls, *P�< 0.05, Townsend score given as median, §per unit

increase in score, ²lifetime prevalence of maternal smoking or non-smoking.

Table 2. Total of RTIs during gestation

of asthmatic children and controls,

showing odds ratios adjusted for all

independent variables. N� 200 in each

group

A C OR (95% CI) Adjusted OR (95% CI)

RTI ®rst trimester 24 11 2.30 (1.05±5.41)* 2.32 (1.01±5.34)²

RTI second trimester 25 22 1.11 (0.56±2.33)

RTI third trimester 19 11 1.70 (0.74±4.15)

Colds/URTI 16 11 1.44 (0.57±3.83)

Cough 39 18 2.24 (1.23±4.22)** 2.29 (1.17±4.48)²

Smoking in pregnancy 27 17 1.44 (0.57±3.83)

Non-smoking in pregnancy 68 67

Non-RTI illness 69 71

Children: hay fever 51 12 7.55 (3.19±21.51)***

Other rhinitis 20 5 3.80 (1.37±13.02)**

Eczema 118 66 2.79 (1.81±4.43)***

A� asthmatics; C� controls, *P < 0.05, **P < 0.01, ***P< 0.001. ²Adjusted for all inde-

pendent variables. Data on smoking in pregnancy available for 47% of asthmatics and 42% of

controls.

Table 1. RTI during gestation of

asthmatic children and age-matched

controls. N� 200 in each group

infection associated with foetal development in a group of

asthmatic children, but as a retrospective study the ®ndings

should be interpreted with caution. The foetus is known to

be affected by certain viral infections, such as rubella, in the

absence of maternal immunity, which would tend to be

variable with respect to respiratory viruses. Viraemia has

been shown to occur in infections with adenovirus and

rhinovirus in infants [11], and with in¯uenza in the incuba-

tion period in adults [12] using the haemagglutination test.

Could respiratory viral particles or antigens cross the

placenta and initiate asthmatic development in the foetus

through the establishment of an `abnormal' foetal immune

response to these viruses?

Acknowledgements

Our grateful thanks are due to Susan Maloney,

Penny Stumbles, Belinda Allis, Rachel Montgomery

and Susan Golding-Cook for collection of data, Dr Ernest

Archer-Koranteng for his participation, Drs Harry Baumer,

Kenneth Buckingham and Richard Cunningham for their

advice, Robert Nelder of South and West Devon Health

Authority for supplying Townsend scores, staff of Plymouth

medical library, and ®nally, Cornwall and Isles of Scilly

Health Authority for their kind donation.

Funding: Cornwall and Isles of Scilly Health Authority.

Con¯ict of interest: none.

References

1 Strachan DP. Hay fever, hygiene, and household size. Br Med J

1989; 299:1259±60.

2 Matricardi PM, Rosmini F, Ferrigno L et al. Cross sectional

retrospective study of prevalence of atopy among Italian

military students with antibodies against hepatitis A virus. Br

Med J 1997; 314:999±1003.

3 Moss N, Carver K. Pregnant women at work: sociodemo-

graphic perspectives. Am J Ind Med 1993; 23:541±57.

4 Johnston SL, Pattemore PK, Sanderson G et al. Community

study of role of viral infections in exacerbations of asthma in

9±11 year old children. Br Med J 1995; 310:1225±9.

5 Pullan CR, Hey EN. Wheezing, asthma and pulmonary dys-

function 10 years after infection with respiratory syncytial

virus in infancy. Br Med J 1982; 284:1665±9.

6 Strachan DP, Butland BK, Anderson HR. Incidence and prog-

nosis of asthma and wheezing illness from early childhood

to age 33 in a national British cohort. Br Med J 1996; 312:

1195±9.

7 Halonen M, Stern D, Holberg C et al. The changing relation-

ship of lower respiratory illness incidence in the ®rst three

years of life to umbilical cord serum IgE levels. Am Rev Respir

Dis 1993; 147 (Suppl.):A15.

8 Warner JA, Miles EA, Jones AC et al. Is de®ciency of

interferon gamma production by allergen triggered cord

blood cells a predictor of atopic eczema? Clin Exp Allergy

1994; 24:423±30.

9 Kondo N, Kobayashi Y, Shinoda S et al. Reduced interferon

gamma production by antigen-stimulated cord blood mono-

nuclear cells is a risk factor of allergic disorders Ð 6 year

follow-up study. Clin Exp Allergy 1998; 28:1340±4.

10 Jones AC, Miles EA, Warner JO et al. Fetal peripheral blood

mononuclear cell proliferative responses to mitogenic and

allergenic stimuli during gestation. Ped Allergy Immunol

1996; 7:109±16.

11 Urquhart GED, Grist NR. Virological studies of sudden,

unexplained infant deaths in Glasgow 1967±70. J Clin Path

1972; 25:443±6.

12 Khakpour M, Saidi A, Na®cy K. Proved viraemia in Asian

in¯uenza during incubation period. Br Med J 1969; iv:208±9.

Respiratory infection during gestation 1381

q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, 1378±1381