The detection of early life factors affecting the risk of asthma can increase our understanding of pathophysiologic mechanisms. In addition, these events can become targets for intervention with a long-term impact.
Both high consumption and early introduction of fish have been suggested to reduce the risk of allergy and asthma development [1-8]. A protective effect on the risk of recurrent wheeze at preschool age has been reported . However, wheezing during the first years of life is a heterogeneous disorder and the prognosis varies . By school age, the diagnosis of asthma is more reliable. At school age, especially atopic asthma is associated with an increased risk of adult asthma .
Antibiotic treatment disturbing the intestinal microbiota in early life might affect the maturation of the immune system and increase the risk of subsequent allergic disease . Treatment with antibiotics during the first year of life has been associated with an increased risk of wheeze, asthma and allergic disease in infancy and at preschool age [7, 11-14]. However, prospective studies up to school age are rare and the possibility of confounding has to be considered [14-16].
The aim of this study was to explore the impact of early life events on the risk of asthma at 8 years, with special reference to the early introduction of fish and treatment with antibiotics neonatally. To avoid reverse causation, only broad-spectrum antibiotics given during the first week of life were considered. In addition, the risk factors for atopic and non-atopic asthma were explored.
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- Supporting Information
In this prospective cohort study, we report a reduced risk of doctor-diagnosed asthma even at 8 years, following the early introduction of fish. Furthermore, treatment with antibiotics during the first week of life increased the risk. The associations were significant for atopic asthma but not for non-atopic asthma. We did no longer see any protective effect from breastfeeding for 4 months or more .
It has been suggested that the protective effect of fish can be attributed to the high content of n-3 polyunsaturated fatty acids (PUFA) in fish . There are some reports of a reduced risk of allergy and eczema in offspring following maternal high n-3 PUFA intake or supplementation with n-3 PUFAs during pregnancy [17, 18]. However, this kind of supplementation in children with heredity for asthma did not prevent subsequent asthma development . There might therefore be other constituents of fish that account for the preventive effect. For example, fish contains vitamin D, which has also been proposed to reduce the risk of allergic disease .
The beneficial effect of fish on asthma and allergy development has been suggested to be explained by reverse causation. In this study, however, the protective effect of the early introduction of fish was independent of, and did not show any significant interactions with, own allergic disease during infancy or parental allergy and asthma. The association in our study can therefore hardly be explained by the later introduction of fish in children with early allergic manifestations or by allergic parents delaying introduction. This is further supported by the findings in a similar setting that the association between early fish consumption and preschool wheeze and eczema remained after excluding children with eczema during the first year of life . We found the effect of early fish introduction both on asthma with an onset before and after preschool age. Thus, the effect did not seem to be due to early risk reduction only. However, we do not know whether this is a long-lasting effect of early fish introduction or explained by early fish introduction being a proxy for continued high consumption of fish.
Finally, it has been suggested that the association is confounded by socio-economic and lifestyle factors . The multivariate model was therefore adjusted for such factors (Table 1).
Antibiotic treatment during the first year of life has been reported to increase the risk of subsequent wheeze and asthma [7, 11-14]. However, there are not many prospective follow-ups into school age. In a recent systematic review, only three studies reported on asthma at school age and the authors called for more prospective studies .
There are findings that support a causal relationship between antibiotic treatment and subsequent asthma. Antibiotic treatment has been reported to change the intestinal microflora, disturbing the maturation of the immune system and affecting the development of immunologic tolerance . The immune response of the newborn is characterized by a Th2 response, and it has been suggested that the maturation towards a Th1 response is stimulated by microbial exposure in early life . It can be speculated that disturbances during this vulnerable period might be of greater importance than later disturbances . In line with these suggested mechanisms, we find an effect on atopic asthma but not on non-atopic asthma at school age.
The absence of effect of antibiotics on incident cases after 4.5 years indicates that the effect of early antibiotics occurred at early years but is still present.
A causal relationship between early antibiotics and subsequent wheeze and asthma has been questioned [14, 15]. Children at risk of developing asthma and allergies have been reported to have a delayed immune maturation already at birth, as well as different cytokine profiles, increasing the risk of infections [24-26]. As a result, the antibiotic treatment might be a marker of increased risk of infections and a disposition to develop asthma. To minimize confounding by post-natal vulnerability, we adjusted for parental allergy and asthma, as well as for preterm birth, caesarean section and being small for gestational age. To avoid reverse causation by treatment of early wheezing episodes with antibiotics, we only considered antibiotic treatment during the first week of life.
The different risk factor profiles for atopic and non-atopic asthma are largely in line with previous findings [27, 28]. Atopic heredity increased the risk of current asthma and non-atopic asthma. However, for atopic asthma, it did not reach significance. The finding of an increased risk of atopic asthma among children born small for gestational age was somewhat unexpected. An association with reduced lung function and asthma has been suggested earlier, but a relation to allergy has been less obvious . However, a recent paper has reported results in line with ours . Atopic asthma was reported among 65% of the children with doctor-diagnosed asthma at school age. Children with atopic asthma tend to have more severe and persistent asthma . Factors associated with atopic asthma suggest an effect mediated via the immune system.
Weaknesses and strengths
Questionnaire-based studies are accompanied by limitations relating to the validity and interpretation of the answers. To avoid this, we have used questions based on well-known, validated questionnaires. As our cohort was not clinically tested, we have defined subjects as having asthma if they reported a doctor's diagnosis of asthma and, in addition, had asthma medication and/or asthma symptoms. Likewise, the definitions of current rhinoconjunctivitis, eczema and food allergy required a doctor's diagnosis, in combination with current medication and/or symptoms. In addition, in absence of blood samples, the classification of atopic and non-atopic asthma was based on reported allergic sensitization or doctor-diagnosed allergic disease. Among the subjects with atopic asthma, 84% reported allergic sensitization. As is often seen in questionnaire studies, responders were somewhat more health conscious and educated compared with non-responders.
The strengths of this prospective follow-up include the large birth cohort size, access to perinatal data and the good response rate at school age.