Clinical & Experimental Allergy
RESEARCH LETTER
Impact of Birth Order on Paediatric Allergic Diseases:
A National Birth Cohort in Japan
Mitsuro Kobayashi1 | Masanori Ikeda2 | Naomi Matsumoto3 | Mitsuru Tsuge4 | Masato Yashiro1 | Takashi Yorifuji3 |
Hirokazu Tsukahara1
1Department of Pediatrics, Okayama University, Graduate School of Medicine, Density and Pharmaceutical Science, Okayama, Japan | 2Department of
Pediatrics, Okayama University Hospital, Okayama, Japan | 3Department of Epidemiology, Okayama University, Graduate School of Medicine, Density
and Pharmaceutical Science, Okayama, Japan | 4Department of Pediatric Acute Medicine, Okayama University, Graduate School of Medicine, Density and
Pharmaceutical Science, Okayama, Japan
Correspondence: Mitsuro Kobayashi ([email protected])
Received: 29 August 2024 | Revised: 9 January 2025 | Accepted: 10 January 2025
Funding: The authors received no specific funding for this work.
Keywords: atopic dermatitis | birth cohort | birth order | bronchial asthma | food allergy
To the editors, calculated after controlling for potential confounders. Subgroup
analysis was also conducted to examine effect modification by
The presence of siblings has previously been reported to have a early daycare attendance, based on whether or not the child was
protective effect on allergic diseases, but the effect remains to attending daycare at the age of 1.5 years. Further analysis was
be elucidated [1]. Our group conducted a longitudinal study of also conducted with an interaction term between birth order
neonates born in 2001 from all over Japan and evaluated the re- and early daycare attendance.
lationships between birth order and each of bronchial asthma,
food allergy and atopic dermatitis [2]. Since then, the prevalence Additional information about study methods and findings are
of childhood allergy in Japan has increased, whereas bronchial available in the following repository: http://doi.org/10.5281/ze-
asthma and atopic dermatitis have started to decline [3]. The en- nodo.14318912.
vironment surrounding allergic diseases has also changed, in-
cluding an increase in the rate of daycare attendance [4]. In this Higher birth order was associated with an increased risk of bron-
study, we surveyed neonates born in 2010 to examine whether chial asthma hospital visits in childhood, but a decreased risk
our findings were temporally robust. during school age (Figure 1A). Compared with first-born chil-
dren, aRR was 2.65 (95% CI 2.23–3.13) at the age of 6–18 months,
We performed a nationwide cohort study using data from the and 0.73 (95% CI 0.60–0.90) at the age of 7–8 years for third-or
21st Century Longitudinal Newborn Survey conducted by later-born children. The risk of food allergy decreased consis-
Japan's Ministry of Health, targeting all babies born in Japan be- tently with higher birth order throughout the investigation pe-
tween 10 May 2010 and 24 May 2010 [5]. Baseline questionnaires riod. Compared with the first-born children, aRR at the age of
for the survey were sent to 43,767 households, of which 38,554 6–18 months was 0.76 (95% CI 0.69–0.84) in the second-born chil-
responded (response proportion, 88%). Follow-up questionnaires dren, and 0.58 (95% CI 0.49–0.68) in the third-or later-born chil-
were sent to the respondents annually thereafter. The outcomes dren. On the other hand, the presence of older siblings increased
were defined as any outpatient visit for these allergic diseases in the risk of atopic dermatitis, particularly in infancy. Compared
each period between 6 months and 9 years of age. Log-binomial with the first-born children, aRR 30–42 months after birth was
linear regression analysis was performed, using first- born 1.39 (95% CI 1.19–1.63) for the third-or later-born children. These
children as a reference, and adjusted relative risks (aRR) were results by disease were similar when stratified by sex.
© 2025 John Wiley & Sons Ltd.
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disease with distinct phenotypes induced by various causes [6].
Summary The finding of a protective effect of birth order in school-age
children is consistent with the hygiene hypothesis. However,
• The relationship between birth order and each allergic
the interaction between birth order and early daycare atten-
disease varied with disease and age.
dance increased the risk for school-age children; hence, fac-
• The protective effect of birth order suggested in- tors, such as timing and intensity of exposure, may be involved
volvement of mechanisms other than the hygiene [7]. Regarding food allergy, the protective effect of birth order
hypothesis.
was observed from early in life, but not in those attending
daycare. This result could not be explained by the hygiene
hypothesis and instead supports the prenatal origin hypoth-
Daycare attendance changed the impact of birth order on bron- esis [1]. However, early weaning initiation, which may serve
chial asthma (Figure 1B). In nonattendees, changes in RR for as a mediator between higher birth order and the development
each allergic disease were broadly similar to those in the entire of allergies, was not considered in this study. Regarding atopic
cohort. On the other hand, among attendees, the risk of bron- dermatitis, both the presence of siblings and daycare atten-
chial asthma in infancy was particularly increased in the first dance were identified as risk factors in this study. These find-
child, reducing the noticeable differences associated with birth ings may reflect the complex pathology of atopic dermatitis,
order. The risk of food allergy in infancy and atopic dermatitis where allergic inflammation and impaired skin barrier func-
during the study period was increased, and there were no appar- tion play interconnected roles [8].
ent associations by birth order.
Despite the large, representative sample size and high response
Despite significant changes in demographic characteristics proportion, this study had several limitations. First, the cohort
and a time difference of 9 years, the results were consistent be- was restricted to children born in May. Second, nearly 40% of
tween the two cohorts [2]. We consider that the increased risk the cohort were lost to follow-up. Third, the study was con-
of asthma in infancy is due to asthma being a heterogeneous ducted in Japan, which limits its generalisability. Fourth, the
FIGURE 1 | Adjusted* RRs for the association between birth order (third-born or later compared to first-born) and allergic diseases: Overall
analysis (A) and stratified by daycare attendance at 1.5 years (B). *Adjusted for child factors (sex, singleton or multiple birth, term or preterm birth),
parental factors (maternal age at delivery, maternal smoking status, maternal educational attainment, and paternal educational attainment), and
residential place of living. *p < 0.05, **p < 0.01, ***p < 0.001, the p-values compared to the first is provided from a test of multiplicative interaction.
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study relied on parental reports, which may not accurately re- 8. M. M. Kusel, P. G. Holt, N. De Klerk, and P. D. Sly, “Support for 2
flect clinical diagnoses. Fifth, while potential confounders were Variants of Eczema,” Journal of Allergy and Clinical Immunology 116
controlled for, residual confounding factors, such as parental al- (2005): 1067–1072.
lergic history, pet ownership or visitation behaviours, may have
influenced the results.
The relationship between birth order and each allergic disease
varied with the disease and age. Further research, including on
the timing and intensity of exposure, is needed to explore these
mechanisms and identify preventive measures for paediatric al-
lergic diseases.
Author Contributions
M.K., M.I. and T.Y. conceptualised and designed this study. N.M. and
T.Y. were involved in data collection and analysis. M.K., N.M. and M.I.
interpreted the data. M.K. and M.I. were involved in manuscript writing
and revision. H.T. supervised the data interpretation. All authors criti-
cally reviewed the manuscript for important intellectual content and
approved the final manuscript.
Ethics Statement
Ethics approval for this study was granted by the Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
and Okayama University Hospital, Ethics Committee (No. 1506-073).
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are openly available in
impact of birth order on pediatric allergic diseases at https://zenodo.
org/, reference number http://doi.org/10.5281/zenodo.14318912.
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