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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 827-832, (2002)
© 2002 American Thoracic Society

Original Articles

The Importance of Prenatal Exposures on the Development of Allergic Disease

A Birth Cohort Study Using the West Midlands General Practice Database

Tricia M. McKeever, Sarah A. Lewis, Chris Smith and Richard Hubbard

Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom

Correspondence and requests for reprints should be addressed to Tricia McKeever, M.Sc., Division of Respiratory Medicine, Clinical Science Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. E-mail: tricia.mckeever{at}nottingham.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The etiology of allergic disease is not understood, but a decreased exposure to infection may play an important role. There are few published data on the impact of change in microbial exposure during pregnancy on the child's risk of developing allergic disease. Using a birth cohort of 24,690 children, derived from the West Midlands General Practice Research Database, we investigated a number of perinatal exposures on the incidence of asthma, eczema, and hay fever. Our findings suggest that exposure to antibiotics in utero is associated with an increased risk of asthma in a dose-related manner (more than two courses of antibiotics compared with none adjusted hazard ratio [HR] 1.68; 95% confidence interval [CI], 1.51–1.87), and similar associations are present for eczema (adjusted HR 1.17; 95% CI, 1.06–1.29) and hay fever (adjusted HR 1.56; 95% CI, 1.22–2.01). Exposure to a range of infections in utero was also associated with a small increased risk of developing allergic disease. Strong protective effects of older siblings on the incidence of allergy are present within this cohort, but previous pregnancies that did not result in a live birth were not protective. Our findings suggest that exposure to antibiotics and to infections in utero is a potentially important risk factor in the development of allergic disease.

Key Words: asthma • epidemiology • hay fever • eczema • perinatal exposures


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The prevalence of allergic disease has increased dramatically in the developed world during the second half of the 20th century, and it has been suggested that this increase is in part due to reductions in early microbial exposure (1). The main evidence for this hypothesis comes from research demonstrating strong protective birth order effects on the risk of having or developing an allergic disease (2–9) and also that exposure to antibiotics early in life increases the risk of developing allergic disease (8, 10–13). Because the immune system develops in utero, factors that modify microbial exposure at this time may have a long-term impact on the risk of developing allergic disease, but research in this area has been limited.

In this study, we have used a birth cohort analysis using data from the West Midlands General Practice Research Database to investigate the relationship between a variety of exposures that alter microbial load during pregnancy, including diagnosis of infections and prescriptions for antibiotics and the incidence of asthma, eczema, and hay fever in the child. We have also taken the opportunity to study the impact of a number of other perinatal exposures, including maternal depression, contraceptive use, and pregnancy complications and have investigated whether pregnancies that do not produce a live child decrease the risk of allergic disease in subsequent children.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cohort
This study uses data from an established birth cohort of children identified historically within the General Practice Research Database, which is the largest longitudinal primary care dataset in the United Kingdom and is based on the computerized records of routine clinical care. The details of the cohort have been described elsewhere (2, 12). Briefly, we identified children who were registered with their general practitioner (primary care doctor) within 3 months of birth and whose medical history contained at least one consultation as an indicator that the child was using this general practitioner for their medical needs. Where possible, we identified mothers, fathers, and older and younger siblings. We then extracted incident diagnoses of asthma, wheeze, eczema, and hay fever using the Oxford Medical Information System, which was derived from International Classification of Disease, version 8, and Read codes, hierarchical codes commonly used in general practices in England.

In this study, we have examined the impact of exposures during pregnancy on the development of allergic disease in the child, and we have defined pregnancy as the period 280 days before date of birth of the child. Using the Oxford Medical Information System and Read codes, we have attempted to identify all infections diagnosed in the mother during pregnancy and have categorized infections using our established methods into gastrointestinal infections, respiratory tract infections, conjunctivitis, otits media, candida, bacterial infection, and viral infections (2). We then extracted data for all prescribed antibiotics during pregnancy and grouped them into the following categories: penicillin, amoxycillin, coamoxiclav, macrolides, cephalsporin, and other antibiotics. We collected information on the timing of antibiotics by trimester and also collected information of the paternal exposure to antibiotics during pregnancy period. Using the mother's records, we also identified any recorded abortions (therapeutic or spontaneous/miscarriages) and stillbirths before the birth of the index child. Other maternal factors were also examined, including the use of contraception (1 year before pregnancy), complications during pregnancy (including antepartum hemorrhage, preterm contractions, and problems with placenta), and maternal depression defined by a diagnosis of disease or prescription for an antidepressant in the time period of 3 months before conception until 3 months after the date of birth of the child. To attain an estimate of the frequency of visits to the doctor, we extracted the number of medical visits recorded in 6-month intervals from birth, excluding visits for vaccinations and allergic disease outcomes. The Scientific Ethical and Advisory Group who govern the use of the General Practice Research Database approved this research.

Statistical Analysis
Cox regression models were used to analyze the impact of exposures on disease incidence and to estimate the hazard ratios (HR) and 95% confidence intervals (CI); diagnoses of wheeze and asthma were analyzed separately and together. Each exposure was initially examined in a series of univariate analyses as binary "exposed or unexposed" indicator variables and then where appropriate as ordered categorical variables to look for evidence of dose–response relationships. We then used multivariate analyses to examine the effect of possible confounders, including gender, parental allergic disease, parental smoking, maternal age, general practice, antibiotics in the first 6 months of life, child's consulting behavior in the first 6 months of life in quartiles, and year of birth. In all analyses, the proportional hazards assumption was examined through the STATA diagnostic command phtest1 (Stata Corporation, College Station, TX), and where the proportional hazard assumption was not met, the HRs were examined on either side of the midpoint of person-year time. All analyses were performed with STATA 7.0 using robust standard errors.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The full cohort contains 29,238 children born between 1988 and 1999 and has marginally more males (n = 14,957, 51%) than females. We were able to identify likely mothers for 84% of the cohort (n = 24,690) (2), and it is these children on whom the rest of the analyses are based. The characteristics of the timing of onset of allergic disease in these children are shown in Table 1 .


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  		TABLE 1. Characteristics of children with identified mothers and diagnosed with disease

 
Approximately one third of the mothers were prescribed one or more courses of antibiotics during pregnancy, and this exposure was associated with an increased incidence of all three allergic diseases (Tables 2 and 3) . There were similar sizes of effects for wheeze and asthma (Table 2). This effect did not appear to depend on the type of antibiotic prescribed or the trimester the antibiotics were prescribed in (data not shown), but there was some evidence of a dose–response effect, especially for asthma. Adjusting for maternal smoking, maternal age, number of older siblings, year of birth, and general practice did not affect the results. Adjusting for the presence of maternal allergic disease and the child's consulting behavior did slightly reduce the size of these effects, and the adjusted values are shown in Tables 2 and 3. When the analysis was restricted to allergic diagnoses after the age of 1 year, we found the impact of having three or more antibiotics in pregnancy virtually unchanged: asthma (adjusted HR 1.59; 95% CI, 1.36–1.87), eczema (adjusted HR 1.22; 95% CI, 1.04–1.42), and hay fever (adjusted HR 1.41; 95% CI, 1.07–1.87). Because we have previously demonstrated an increase in the risk of allergic disease in children if they are exposed to antibiotics in the first year of life (12), with the addition of exposure to antibiotics in the first year of life to the adjusted models, having three or more antibiotics in pregnancy was still associated with HR for asthma (1.36; 95% CI, 1.16–1.60), eczema (1.19; 95% CI, 1.02–1.39), and hay fever (1.33; 95% CI, 1.00–1.77). There was no relationship between the use of antibiotics in the father during the pregnancy period and the incidence of disease in the child.


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  		TABLE 2. Use of antibiotics in pregnancy and the incidence of doctor-diagnosed wheeze, asthma, or either

 

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  		TABLE 3. Use of antibiotics in pregnancy and the incidence of doctor-diagnosed eczema and hay fever

 
The most common infections diagnosed during pregnancy were respiratory tract infections and candida, both diagnosed in 14% of mothers (Table 4) . A recorded diagnosis of infection in all categories during pregnancy was associated with a general increase in the incidence of asthma, eczema, and hay fever. The size of these effects were small, but adjusting for maternal smoking, maternal age, number of older siblings, maternal allergic disease, year of birth, and general practice did not alter the HRs. Adjusting for child consultation in the first 6 months of life reduced the size of these effects by approximately 10%, and the adjusted HRs are shown in Table 4. There was also a small dose–response relationship with the total number of infections that a mother was diagnosed with in pregnancy. In keeping with our analyses for maternal antibiotics, separating diagnoses into wheeze or asthma did produce any difference in the estimates of the HRs, and analyzing the data for disease occurrence after the age of 1 year produced similar results (data not shown).


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  		TABLE 4. Maternal infections in pregnancy and the development of allergic disease*

 
When the impact of antibiotics and infection was modeled simultaneously, the use of antibiotics slightly attenuated the relationship between infections and risk of allergic disease (Table 5) , and the association with bacterial infections disappeared, although adjusting for infection in pregnancy did not notably affect the relationship between antibiotic use and the risk of all three allergic diseases.


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  		TABLE 5. Impact of antibiotics and infection on allergic disease in a mutually adjusted model

 
The results from the other maternal exposures are shown in Table 6 . Previous pregnancies in the mother that were either spontaneous or therapeutic abortions did not appear to affect the incidence of allergic disease in subsequent children nor did previous stillbirths. The use of oral contraception in the year before conception was associated with a small increase in asthma (HR 1.10; 95% CI, 1.03–1.17) and eczema (HR 1.07; 95% CI, 1.02–1.12) incidence, although this effect was no longer significant with adjustment for the child's consulting behavior. Only 1% of the mothers had complications during pregnancy recorded, although despite the small prevalence of this exposure, an association with an increased risk of developing asthma (HR 1.62; 95% CI, 1.23–2.14) was found, and marginal effects for eczema (HR 1.27; 95% CI, 0.98–1.63) and hay fever (HR 1.50; 95% CI, 0.80–2.80) were also present. These relationships were similar when mothers with asthma and without asthma were analyzed separately. A diagnosis or treatment for depression in the mother was associated with an increased risk of developing all three allergic diseases, and adjusting for maternal atopy, maternal smoking, or maternal age did not affect these results (Table 4), although adjusting for consulting behavior of the child in the first 6 months did reduce the size of these effects such that the relationship for asthma was 1.26 (95% CI, 1.16–1.37), eczema was 1.03 (95% CI, 0.96–1.11), and hay fever was 1.10 (95% CI, 0.90–1.35).


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  		TABLE 6. Univariate associations between perinatal exposures and the incidence of doctor-diagnosed allergic disease

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our results suggest that exposure to antibiotics in utero is associated with a dose-related increase in the child's risk of allergic disease, and we found similar though smaller effects for exposure to infections. We have already reported that there are strong birth order effects within this cohort (2), but previous pregnancies that did not lead to a live birth did not protect against the development of allergic disease in the child. Perinatal maternal depression was associated with an increased risk of having a diagnosis of all three allergic diseases, particularly asthma. Finally, complications in pregnancy were associated with an increased risk of asthma, but not for eczema or hay fever.

There are a number of advantages and disadvantages to using general practice data such as the General Practice Research Database for research. Our case definition is based on doctor-diagnosed disease. Although this approach has been used for many other research studies, our case definition was dependent on the child going to the doctor and receiving a diagnosis. A major factor to consider, therefore, is ascertainment bias; that is, families who tend to consult the doctor more frequently may be more likely to have both exposures recorded and diagnoses made, thereby producing a positive association. To address this problem, we have adjusted our analyses for consulting behavior, but as children must consult to receive a diagnosis, it is possible that by adjusting for consulting behavior we have "overadjusted" our analyses making our results conservative. There are no specific markers of social class with the General Practice Research Database, but we have investigated whether maternal smoking, which is related to social class, is a confounding factor and found no evidence for it. In addition, our marker of infection is based on doctor-diagnosed disease and therefore will not contain all exposure to infection, although we suspect that during pregnancy a mother is more likely to consult over infections because of concerns for her baby's health.

Our findings of a relationship between exposure to infections in general during pregnancy and an increased risk of allergic disease are consistent with previous research, which has demonstrated that infections in the first trimester of pregnancy are associated with an increased risk of allergic disease (14, 15). These data are clearly not in keeping with the hygiene hypothesis, which suggests that exposure to early infections may be protective.

Antibiotics can cross the placenta and enter the fetal circulation (16), and there are data that suggests that exposure to antibiotics early in life may increase the child's risk of developing allergic disease (8, 10–13). We found a dose–response relationship between antibiotics given during pregnancy and the child's risk of developing an allergic disease, and to our knowledge, this is the first time that this association has been reported. Although the dose–response evidence points toward a causal relationship, it is possible that some ascertainment bias is present, although adjusting for consulting behavior had only a minor effect. To try to examine the impact of family consulting behavior further, we have looked at paternal antibiotics in the pregnancy period, and here we found no associations.

The presence of older siblings has consistently been shown to decrease the incidence of allergic disease, and this is true in this cohort; however, we and others have not been able to explain this effect in terms of early life exposure such as infection (12), and similarly, antibiotics or infections in pregnancy are not the reasons (6, 10, 17). An alternative explanation for the birth order effects is that they are mediated by pregnancies changing the mother. A cross-sectional study has found that women who had a greater number of children were less likely to be atopic (18), and a cohort study found that cord blood immunoglobulin E levels were higher in children with older siblings and that cord blood immunoglobulin E was a better predictor than number of older siblings for atopic sensitization at the age of 4 years (19). In this study, we found no evidence that previous pregnancies terminated through a therapeutic or spontaneous abortion reduced the risk of allergic disease in subsequent children. It is possible that a protective effect of pregnancy occurs only if the baby is carried to term, but against this is the fact that we were unable to detect a protective effect with stillbirths, although there was limited statistical power for this analysis. However, our data suggest that it is exposure to living older siblings rather than the number of pregnancies themselves that is important.

We found a small association between use of contraception in the 12 months before conception and developing of allergic disease and in keeping with one previous study (15), although our effect disappeared after adjusting for consulting behavior, suggesting that this may be due to ascertainment bias. It has been shown that cord blood immunoglobulin E was significantly higher in mothers that were taking progesterone therapy during pregnancy (20). Given the higher incidence of allergic disease in boys compared with girls and the impact of estrogens and progesterone levels during pregnancy, this is an area that requires more research.

A number of studies have found evidence of a relationship between atopic disease and affective disorders (21–27). Our results suggested that maternal depression may increase the incidence of the child's allergic diseases, particularly asthma. Clearly, ascertainment bias may explain some of this relationship, but our findings are supported by others who have shown that parental stress early in life increases the child's risk of asthma (28–31) and raises both maternal and cord blood immunoglobulin E and invokes a Th2-dominated environment in utero (32).

In this study, we found evidence that complications recorded during pregnancy increased the incidence of all three allergic diseases, particularly asthma. Because maternal allergic disease is an important risk factor for child allergy (2) and mothers with asthma may have more complications during pregnancy (33–35), maternal allergy will be an important confounder in the analysis. The size of our effects was unchanged by adjusting for maternal allergic status, however, and similar impacts of pregnancy complications were present when mothers with and without asthma were analyzed separately. The data therefore suggest that pregnancy complications are an independent risk factor for allergy, and these findings are consistent with previous research, which found a relationship between complications in pregnancy and a child's risk of developing allergic disease (15, 36, 37).

In summary, our research suggests that exposures, which modify microbial load during pregnancy, may increase a child's risk of developing allergic disease. Some of these exposures, particularly the use of antibiotics, are potentially avoidable, and thus, further research into the impact of these exposures on the incidence of allergic disease is required. The presence of pregnancies that do not lead to a live birth do not protect against the risk of developing allergic disease, suggesting that the birth order effects seen in this and other cohorts are mediated by exposure to live older siblings, rather than changes in maternal physiology.


   Acknowledgments
 
The authors are grateful to the Department of Medicines Management, Keele University, for providing access to the West Midlands General Practice Research Database for use in this project.


   FOOTNOTES
 
Supported by the National Asthma Campaign.

Received in original form February 27, 2002; accepted in final form June 20, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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B. W. Kramer, M. Ikegami, T. J. M. Moss, I. Nitsos, J. P. Newnham, and A. H. Jobe
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C. Cohet, S. Cheng, C. MacDonald, M. Baker, S. Foliaki, N. Huntington, J. Douwes, and N. Pearce
Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood
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S. Foliaki, S. K. Nielsen, B. Bjorksten, E. von Mutius, S. Cheng, N. Pearce, and the ISAAC Phase I Study Group
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J. Pekkanen
Commentary: Use of antibiotics and risk of asthma
Int. J. Epidemiol., June 1, 2004; 33(3): 564 - 565.
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M. Thomas, D. Price, T. McKeever, S. Lewis, and R. Hubbard
Prenatal antibiotic exposure and subsequent atopy
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M. J. Tobin
Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2002
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M. J. Tobin
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002
Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 333 - 344.
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