Systematic Exploration of Birth Season-Associated Pediatric Diseases in Hangzhou, China: A Retrospective Observational Study

Systematic Exploration of Birth Season-Associated Pediatric Diseases in Hangzhou, China: A Retrospective Observational Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Systematic Exploration of Birth Season-Associated Pediatric Diseases in Hangzhou, China: A Retrospective Observational Study Yuqing Feng, Qiang Shu, Haomin Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7212492/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Season of birth (SOB) has been associated with various pediatric diseases, but previous studies often focus on a limited number of diseases. Therefore, this study comprehensively and systematically investigates the associations between SOBs and numerous common pediatric diseases. Methods This was a retrospective observational study of 3,480,838 children (age100) and SOBs by chi-square test with Bonferroni correction, odds ratios (ORs) from adjusted logistic regression models (adjusted for sex, age, and visit season) and prevalence ratios (PRs, SOB vs the other 3 SOBs). Results A total of 360 significant associations across 179 SOB-associated diseases (details at http://pedmap.nbscn.org/birth.html), including 146 novel diseases and 33 previously reported diseases, were identified. Spring births were only positively significant associated with tinea versicolor (PR=-0.54). The strongest positive association was observed between seborrhoeic infantile dermatitis and autumn births (OR=4.03, 95% CI 2.42 to 6.69; PR= 0.52). Additionally, the effects of SOBs on disease risk varied significantly between sexes, particularly for disorders of fatty-acid metabolism (boys: OR=3.01 vs girls: OR=1.98) and seborrhoeic infantile dermatitis (boys: OR=3.47 vs girls: OR=5.39) in autumn births, G6PD deficiency (boys: OR=1.69 vs girls: OR=3.15) in summer births, and all kinds of inguinal hernias in winter births. Conclusions This systematic investigation corroborated previous findings and identified novel associations between pediatric diseases and SOB. Children born in autumn and winter may be at greater risk for various diseases, with some diseases exhibiting notable sex disparities in their associations with SOBs. These insights highlight the importance of considering seasonal and sex-related factors in pediatric disease prevention and management strategies. seasons of birth risks of diseases odds ratios epidemiology pediatrics Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Background Seasons of birth (SOBs) influence childhood and lifelong health by acting as proxies for prenatal and early postnatal environmental exposures [ 1 , 2 ]. Seasonal variations in temperature, humidity, pollen levels, ultraviolet radiation intensity, and air pollution during gestation and infancy may impact developmental pathways and physiological outcomes [ 3 – 5 ]. Therefore, understanding the epidemiological associations between SOBs and common pediatric diseases is crucial for developing targeted strategies. Previous studies have revealed associations between SOBs and various pediatric diseases. For example, children born in the winter have a 16% greater risk of stunting than do those born in the spring and are more susceptible to asthma between the ages of 2 and 6 [ 6 , 7 ]. Similarly, autumn and winter births are associated with an increased risk of early-onset food allergies, particularly to hen eggs, cow milk, and wheat [ 8 ], as well as a greater likelihood of autism spectrum disorder [ 9 ]. Other diseases, such as schizophrenia [ 10 ], attention deficit/hyperactivity disorder (ADHD) [ 11 ], atopic dermatitis [ 12 ], and hand-foot-mouth disease [ 13 ], have also shown significant seasonal associations. Collectively, these findings underscore the profound impact of SOB on health outcomes, suggesting that birth timing may shape a child's health trajectory. However, previous studies have often focused on a narrow range of diseases, such as allergies, subclinical psychosis, and mental disorders [ 4 , 14 – 16 ]. Thus, this study aimed to complete a comprehensive, large-scale epidemiological study of SOB associations with a wide range of pediatric diseases, using data from millions of pediatric outpatient visits accumulated over time. 2. Methods 2.1 Data and Population Data from pediatric outpatient visits, including birth date, gender, visit time, and diagnosis, were collected from a tertiary children’s hospital with four branches in Hangzhou, Zhejiang Province. Diagnoses for each pediatric outpatient visit were recorded via the International Classification of Diseases, version 10 (ICD-10) codes. Each ICD code had a corresponding outcome—a binary variable. There are two values of outcome: patients with disease often have an outcome equal to 1, and those without disease often have an outcome equal to 0. This study included 10,167,101 pediatric outpatient visits (age<18) recorded from 2014-2021, representing 3,480,838 unique children (57.01% boys) and 7,971 distinct diagnoses. The demographic distribution of the study population is shown in supplemental Table S1. SOBs were constructed from the seasonal distribution of Hangzhou: spring (March-May), summer (June-August), autumn (September-November), and winter (December-February). The distribution of SOBs was slightly uneven, with more children born in autumn (26.94%, n=938,947) and fewer born in spring (23.00%, n=800,700). 2.2 Analysis Fig. 1 illustrates the flowchart applied to identify these associations. We employed odds ratios (ORs), 95% confidence intervals (95% CIs), and p-values from chi-square test, Bonferroni correction tests, and logistic regression models to evaluate these associations with the primary exposure to SOBs [17]. The statistical workflow was as follows: Data filtering: Diseases with more than 100 patients were included to ensure statistical power. Chi-square test with Bonferroni correction: identified diseases with significant variation across SOBs. Confounder control: We excluded 12 neonatal diseases (ICD-10: P00-P96) and 8 health service-related diseases (ICD-10: Z00-Z99) to avoid confounding by birth season, visit season and routine medical checkup bias. Logistic regression: Multiple logistic regression models with SOBs adjusted for Age, Visit Season, and Sex. Ultimately, diseases that passed all tests in the statistical workflow (p-values<0.05) were deemed to have significant associations with SOBs. The criteria for substantial associations between diseases and SOBs were as follows: P-values<0.05 in all tests (p-value1.5 (positive) or OR<0.5 (negative) To assess seasonal disease risk, we calculated the prevalence ratio (PR) to evaluate the effects of all 4 SOBs on diseases with substantial associations: where represents the prevalence of the disease in the aim SOB. represents the prevalence of the disease in the other 3 SOBs. PR was the maximum value for each disease in the 4 SOBs. We also explored the relationship between PR and the mean age of patients with each disease. A higher PR indicates a greater risk of disease in the target SOB than in other SOBs. Our analysis also conducted stratified analyses to evaluate disease associations in boys and girls separately and calculated the mean age for each disease. All analyses were performed in R (v4.3.3). 3. Results In this study, 1,396 diseases with sufficient patients (with more than 100 patients) were categorized into 21 groups on the basis of their ICD-10 codes (supplemental Table S2). We described the distribution of patient visits (supplemental Fig. S1 ). There was a sex disparity in patient visits for different types of diseases. We constructed a Manhattan plot depicting the significance of associations between SOBs and 1,396 diseases, as shown in Fig. 2 (a). A total of 179 diseases were significantly associated with SOBs (including 20 types of diseases), resulting in 360 specific associations across different SOBs in the whole study population. The details of these diseases and associations are provided at http://pedmap.nbscn.org/birth.html . To enhance the clarity of the figure, Fig. 2 (b) shows the heatmap of partially significant associations (using the complete linkage clustering method), with ORs > 1.2 or ORs < 0.8. In Fig. 2 (b), diseases were grouped into five distinct clusters: Low-risk cluster for autumn: Diseases with lower risk in the autumn birth cohort typically also had low risk in the winter (or summer) birth cohort. High-risk cluster for autumn: 13 diseases that were significantly positively associated with only the autumn birth cohort. High risks for both summer and autumn: Diseases with high risks in both the summer and autumn birth cohorts, with the autumn birth cohort showing significantly higher risks. High-risk cluster for autumn and winter: Diseases with higher risks in both the autumn and winter birth cohorts, with the autumn birth cohort showing slightly higher risk. High-risk cluster for summer, autumn, and winter: Diseases with high prevalence across all SOBs (except spring). Overall, children born in autumn were associated with most pediatric diseases. Moreover, tinea versicolor (B36.000) and astigmatism (H52.200) had negative associations across summer, autumn, and winter. Additionally, digestive system diseases had the highest risk, which was typically observed in the autumn birth cohort, followed by the winter birth cohort. 3.1 SOBs and diseases (spring was the reference group) Among the 360 significant associations, 38 were classified as substantial, involving 29 diseases. Table 1 summarizes the substantial associations (OR > 1.5 and OR 1.5), whereas tinea versicolor (B36.000) was negatively associated with autumn births (OR < 0.5). Notably, all 28 positively associated diseases were diagnosed earlier in the corresponding SOBs than in whole disease cohort. Table 1 Substantial associations between SOB and diseases in all patients SOB ICD-10 Mean Age Mean Age* Counts Counts* OR (95%CI) Significant positively associated diseases Summer L21.100 0.24 0.34 42 144 2.38(1.42,4.00) G71.200 1.64 3.06 94 248 2.03(1.42,2.93) E74.002 0.28 0.34 438 1,261 1.93(1.31,1.67) J21.900 0.55 0.68 192 608 1.82(1.44,2.31) R17.x00 0.15 0.22 10,359 38,121 1.76(1.71,1.81) Autumn L21.100 0.47 0.34 57 144 4.03(2.42,6.69) R17.x00 0.24 0.22 9,654 38,121 2.65(2.57,2.74) E71.300 0.29 0.31 337 1,174 2.43(2.05,2.90) E74.002 0.46 0.34 324 1,261 2.34(1.98,2.76) M16.301 1.23 0.99 422 1,231 2.19(1.86,2.58) Q31.500 0.84 0.49 463 1,637 2.16(1.86,2.49) H60.501 0.96 0.65 577 1,908 2.06(1.81,2.35) E80.604 0.56 0.54 579 1,924 2.05(1.81,2.34) K40.903 2.41 2.29 150 465 2.01(1.51,2.68) K42.900 0.70 0.56 2,235 7,920 1.94(1.92,2.07) H04.401 0.80 0.46 3,969 14,494 1.93(1.84,2.03) H04.509 0.81 0.53 4,443 16,005 1.81(1.73,1.89) K40.309 1.38 1.27 117 354 1.80(1.33,2.44) K40.306 1.70 1.41 105 321 1.80(1.30,2.48) K40.312 1.46 1.39 225 732 1.73(1.40,2.15) K40.314 1.63 1.37 620 1,984 1.72(1.51,1.96) R68.101 0.78 0.56 3,218 11,612 1.71(1.62,1.81) Q17.302 1.09 0.97 436 1,511 1.68(1.45,1.95) J21.900 0.98 0.68 171 608 1.67(1.31,2.13) M16.900 1.10 0.74 17,744 65,041 1.60(1.57,1.64) S73.001 1.27 1.04 362 1,168 1.59(1.35,1.87) Q65.801 1.10 0.77 2,164 7,754 1.53(1.44,1.63) Q65.200 2.55 2.01 186 581 1.52(1.21,1.92) E71.302 0.63 0.70 292 960 1.50(1.26,1.80) Winter K40.903 2.01 2.29 160 465 2.23(1.68,2.97) K44.901 1.98 2.29 164 425 1.87(1.43,2.44) K40.309 1.15 1.27 115 354 1.68(1.24,2.27) K40.314 1.17 1.37 631 1,984 1.61(1.41,1.83) K40.306 1.44 1.41 102 321 1.60(1.16,2.21) K40.312 1.26 1.39 231 732 1.60(1.30,1.99) E02.x00 2.20 2.47 210 619 1.52(1.22,1.90) E03.100 1.01 1.14 9,208 25,171 1.51(1.46,1.56) Significant negatively associated diseases Autumn B36.000 4.23 1.84 656 2,835 0.34(0.30,0.38) Note: Spring was the SOB set as the reference in the analysis. Mean Age was the mean age of patients with the disease who were born in a season at the first visit; Mean Age* was the mean age of patients with the disease at the first visit; Counts was the number of patients who had the disease and were born in a season; Counts* was the number of patients who had the disease. 3.1.1 Born in Spring As shown in Table 1 , autumn newborns had a 66% lower risk of tinea versicolor (B36.000) than did spring newborns (OR = 0.34, 95% CI: 0.30, 0.38). Similarly, summer-born and winter-born children had 42% (OR = 0.58, 95% CI: 0.53, 0.64 for summer births) and 41% (OR = 0.59, 95% CI:0.54, 0.65 for winter births) lower risks, respectively, although these associations did not meet the threshold for substantial association. Notably, tinea versicolor was the only disease in Table 1 that had a substantial negative association with all SOBs, with spring births used as the reference. 3.1.2 Born in Summer Compared with autumn and winter, being born in summer was positively associated with the fewest diseases. As shown in Table 1 , seborrhoeic infantile dermatitis (L21.100), congenital myopathy (G71.200), G6PD deficiency (E74.002), acute bronchiolitis (J21.900) and jaundice (R17.x00) were strongly associated with children born in the summer. Notably, the greatest OR among these diseases occurred between seborrhoeic infantile dermatitis (L21.100) and children born in summer (OR = 2.38, 95% CI: 1.42, 4.00), although only 144 patients were diagnosed with this disease (29.17% were born in summer). In addition, summer environmental exposure at infancy poses a significant risk for all diseases, except congenital myopathy (G71.200), for which the mean age of these patients is close to 0 years. 3.1.3 Born in Autumn In contrast to summer births, autumn births were associated with the highest number of positively associated diseases, many of which were related to the digestive system. These included sliding inguinal hernia (K40.903), umbilical hernia (K42.900), incarcerated inguinal sliding hernia (K40.309), unilateral incarcerated indirect inguinal hernia (K40.306), incarcerated inguinal hernia (K40.312), and incarcerated indirect inguinal hernia (K40.314). Fortunately, most of them had relatively few patients and a relatively high mean age. However, umbilical hernia (K42.900) stood out as a disease of concern, with a relatively younger mean age (Mean Age = 0.70) and a greater number of affected infants (Counts = 2,235, Counts* = 7,920). Similar to summer-associated diseases, the greatest OR was observed between seborrhoeic infantile dermatitis (L21.100) and children born in autumn (OR = 4.03, 95% CI: 2.42, 6.69). Hip-joint disease (M16.900) was another disease significantly positively associated with autumn births, with the highest number of affected patients (Counts = 17,744, Counts*=65,041). 3.1.4 Born in Winter 8 diseases were substantial significant positive associated with winter-born children. Among these diseases, many digestive diseases associated with autumn births, including sliding inguinal hernia (K40.903), incarcerated inguinal sliding hernia (K40.309), incarcerated indirect inguinal hernia (K40.314), unilateral incarcerated indirect inguinal hernia (K40.306), and incarcerated inguinal hernia (K40.312), were also positively associated with winter births. Among these, sliding inguinal hernia (K40.903) had the greatest OR (OR = 2.23, 95% CI: 1.68, 2.97). Hiatus hernia (K44.901) was the only digestive disease significantly positively associated with winter-born children (OR = 1.87, 95% CI: 1.43, 2.44). In addition to digestive diseases, endocrine, nutritional, and metabolic diseases had higher risks for winter-born children, with congenital hypothyroidism (E03.100) affecting more patients (Counts = 9,208, Counts*=25,171). 3.2 Seasonal Disease Risk Patterns Figure 3 shows the seasonal distribution of the 29 substantially associated diseases (OR > 1.5 or OR < 0.5) with the maximum PR. Notably, spring births consistently demonstrated the safest population, with only tinea versicolor (B36.000) exhibiting significantly high risk (PR = 2.25) in this SOB. In contrast, autumn and winter births presented greater disease burdens, with 9 and 13 high-risk diseases, respectively. Risks for winter-born children were predominantly driven by hernias (PR range was 1.38–1.87; the Count range was 102–2,132 across 7 types) and congenital hypothyroidism (PR = 1.71, Counts = 9,208), and the risks of these diseases in winter births were obviously greater than those in children born in other SOBs. In the susceptible population, jaundice was the disease with the lowest mean age (Mean Age = 0.15 in summer births), and congenital hypothyroidism was the disease with the greatest number of patients (Counts = 10,359 in winter births). In general, each SOB showed distinct high-priority diseases, namely, tinea versicolor (spring), jaundice (summer), hip joint disease (autumn), and congenital hypothyroidism (winter), all characterized by high prevalence (higher PR and more patients) and early onset (mean age at diagnosis below 2 years old). 3.3 Novel associations and reported associations To identify novel associations, we conducted a search on PubMed via the keywords “birth season”, “season of birth”, and the names of SOB-associated diseases. Table 2 compares the significant positive associations identified in our study with those reported in previous studies (the references were list in Table S3). As shown in Table 2 , 33 diseases‒SOB associations have been previously reported in studies, with 19 consistent with our findings and 14 showing variations. Table 2 Comparison of significant positive associations in both this study and previous studies ICD-10 (In this study) SOB with highest risk (In this study) Diseases (In previous studies) SOB with highest risk (In previous studies) Consistent Association C95.900 Winter Acute leukemia Winter E02.x00 Winter Subclinical hypothyroidism Winter E03.100 Winter Congenital hypothyroidism Winter F90.900 Summer ADHD Summer G71.200 Summer Idiopathic inflammatory myopathy August H60.501 Autumn Atopic dermatitis Autumn J18.000 Autumn Bronchiolitis Autumn K40.900 Winter Congenital inguinal hernia Winter L20.900 Autumn Atopic dermatitis Autumn L30.902 Autumn Atopic dermatitis Autumn M16.900 Autumn Hip joint development and morphology Autumn M98000/3 Winter Acute leukemia Winter Q24.900 Autumn Congenital heart defects Autumn Q65.200 Autumn Congenital hip dislocation Autumn Q65.801 Autumn Developmental dysplasia of the hip Autumn Q74.102 Autumn Newborn hip dysplasia Autumn R32.x01 Summer Monosymptomatic nocturnal enuresis Summer S73.000 Autumn Newborn hip dysplasia Autumn S73.001 Autumn Developmental dysplasia of the hip Autumn Inconsistent Association B08.401 Winter Hand, foot, and mouth disease April-July E03.900 Winter Autoimmune hypothyroidism Summer E25.004 Autumn Newborn congenital adrenal hyperplasia Winter E46.x00 Winter Severe acute malnutrition Postharvest season and immediate pre-planting season E80.604 Autumn High total serum bilirubin October-March F80.000 Summer Specific speech articulation disorders October–December F81.900 Summer Learning disabilities January-March J21.900 Summer Bronchiolitis Autumn J45.900 Summer Asthma Autumn K52.915 Autumn Crohn’s disease Spring Ulcerative colitis Summer K52.916 Autumn Rotavirus diarrhea Summer M16.301 Autumn Developmental dysplasia of the hip September-January R17.x00 Autumn Total serum bilirubin October-March R94.600 Winter Graves’ hyperthyroidism Males in Winter and females in Spring and Autumn or none Hashimoto’s hyperthyroidism Winter Several diseases from the previous literature aligned with our results, including subclinical hypothyroidism (E02.x00), congenital hypothyroidism (E03.100), congenital myopathy (G71.200), external ear eczema (H60.501), hip-joint disease (M16.900) and subluxation of the hip (S73.001). On the other hand, some diseases associated with SOBs, such as hyperbilirubinemia (E80.604), acute bronchiolitis (J21.900), jaundice (R17.x00) and dysplastic unilateral coxarthrosis (M16.301), presented divergent results in our study. These discrepancies are not unexpected, as seasonal variations can differ between regions due to different local climate patterns. In addition to the reported associations, we identified 146 diseases with no previously documented associations with SOBs in previous studies. Figure 4 (a) shows the distributions of the prevalence rates and ORs of these diseases, many of which had relatively low prevalence rates, or the magnitude of the effect was not large enough to have drawn attention in previous studies. However, some diseases, such as seborrhoeic infantile dermatitis (L21.100), disorders of fatty-acid metabolism (E71.300), G6PD deficiency (E74.002), congenital laryngeal chondromalacia (Q31.500), and sliding inguinal hernia (K40.903), deserve more attention because of their higher ORs (ORs > 2.0) and earlier onset ages. Compared with other diseases, as shown in Fig. 4 (b), more novel SOB-associated diseases (OR > 1.5 or OR < 0.5) were diseases of the digestive system, whereas more reported SOB-associated diseases were endocrine, nutritional, and metabolic diseases. More SOB-associated diseases had modest effects (OR range: 0.8–1.2) and low population prevalence (< 0.005). 3.4 Sex disparity Some diseases show sex-specific differences, indicating that the effects of SOB may vary by sex. In this study, some obvious sex disparities in the associations between SOBs and several diseases, such as disorders of fatty-acid metabolism (E71.300), G6PD deficiency (E74.002), inguinal hernias (K40) and seborrhoeic infantile dermatitis (L21.100), were identified. Disorders of fatty-acid metabolism (E71.300) had a greater risk in autumn-born boys (OR = 3.01) than in autumn-born girls (OR = 1.98). Similarly, hernias (K40.306, K40.309, K40.312, K40.314, K40.903, K42.900, and K44.901) presented statistically significant differences in SOBs among boys. Autumn-born boys had increased risks of unilateral incarcerated indirect inguinal hernia (OR = 1.74 for K40.306), incarcerated inguinal sliding hernia (OR = 1.93 for K40.309), and sliding inguinal hernia (OR = 2.18 for K40.903). Winter-born boys had greater risks of incarcerated inguinal sliding hernia (OR = 1.73 for K40.309) and incarcerated inguinal hernia (OR = 1.66 for K40.312), whereas no such trend was observed in girls. For seborrhoeic infantile dermatitis (L21.100), autumn-born girls had a significantly greater risk (OR = 5.39) than did those born in other seasons, whereas autumn-born boys had a moderately high OR of 3.47 than did those born in other seasons. Similarly, G6PD deficiency (E74.002) was markedly more common in summer-born girls (OR = 3.15) than in those in other seasons, whereas summer-born boys had a moderate increase in risk (OR = 1.69). 4. Discussion Comprehending early-life environmental determinants of pediatric disease is essential for advancing biomedical research. Our study systematically validated and expanded the list of diseases associated with SOBs. Overall, those born in autumn and winter were more susceptible to numerous diseases, particularly various types of hernias (K40-K44), which presented higher ORs (and PRs) and affected a greater number of patients. In contrast, spring was significantly positively associated with only tinea versicolor (B36.000). Additionally, some diseases, such as disorders of fatty-acid metabolism (E71.300), G6PD deficiency (E74.002), and seborrhoeic infantile dermatitis (L21.100), exhibit sex-specific risk variations. Children born in autumn are at increased risk for a variety of diseases, including skin diseases (e.g., L21.100) and metabolic diseases (e.g., E71.300). A plausible explanation is that autumn births may influence postnatal immune system maturation [ 18 ]. Winter-born children presented elevated risks primarily for hernias and congenital hypothyroidism. Congenital hypothyroidism has been reported to be associated with winter births [ 19 ]. Its high risk may be caused by low temperatures in winter. Previous studies have shown that exposure to low temperatures in the final weeks of pregnancy can increase the risk of congenital hypothyroidism [ 20 ]. Additionally, insufficient sunlight exposure and UVB radiation may lead to vitamin D deficiency, adversely affecting both maternal and fetal thyroid function [ 21 , 22 ]. In this study, inguinal hernias (with 56,781 patients) occurred predominantly at 1–3 years of age, likely because of intra-abdominal organ development and increased abdominal pressure as children begin to walk. High weight may exacerbate this risk [ 23 ]. A previous systematic review also revealed that individuals born in cold seasons had higher body mass indexes (BMIs) and weights in childhood, potentially explaining the increased risk of inguinal hernias in toddlers during autumn and winter [ 24 ]. Additionally, the risk of inguinal hernias in SOBs also varies by sex, with boys demonstrating stronger SOB associations than girls do—a pattern inconsistent with established epidemiological trends [ 25 , 26 ]. One explanation is the anatomical distinctions in the inguinal region: boys have wider and thinner inguinal canals due to the descent of the testes during embryonic development, making them more prone to intestinal protrusion and hernia formation [ 23 ]. G6PD deficiency was another notable disease that also varied by sex in our study. We found that girls born in the summer had a particularly greater risk of G6PD deficiency (summer-born girls, OR = 3.15; summer-born boys, OR = 1.69). As an X-linked genetic trait, G6PD deficiency has lower diagnostic thresholds in males (XY) than in females (XX) [ 27 , 28 ]. The G6PD enzyme activity exhibited significant seasonal differences, reaching its minimum in summer due to high temperatures [ 29 ]. Another study suggested that the high temperature and humidity of summer can reduce G6PD enzyme activity in blood samples, increasing the risk of false positives for G6PD deficiency in summer births [ 30 ]. Consequently, these factors may disproportionately affect girls, as their enzyme activity thresholds are more sensitive to seasonal variations, and they are more likely to meet the cutoff for deficiency in summer births. Among the novel findings in this study, the strongest positive association was observed between infantile seborrheic dermatitis and autumn births. This disease, most common in infants under 1 year of age, peaks at approximately 3 months of age [ 31 ]. A potential mechanism involves seasonal effects on the colonization of Malassezia , a lipophilic commensal bacterium that colonizes human skin and reaches the adult type 30 days after birth [ 32 , 33 ]. Dry autumn air may promote the transformation of Malassezia from round blastospores to a mycelial form, exacerbating the disease [ 34 ]. This hypothesis is supported by the young mean age of affected infants and the efficacy of antimycotic treatments in reducing Malassezia levels and disease recurrence [ 34 , 35 ]. Our study has several notable strengths. First, to our knowledge, this is the first large-scale epidemiological study to comprehensively assess the risk of 1,396 common pediatric diseases associated with different SOBs in Hangzhou city. Second, we applied multiple rigorous statistical methods, including multiple testing corrections and stratified analyses by sex, to ensure robust findings. Third, we identified 146 novel and 33 previously reported SOB-associated diseases. However, this study has several limitations. First, it is a single-center study, which means that these findings may not apply to other regions with different seasonal characteristics. Second, this study focused on pediatric diseases and omitted those that manifested in adulthood. Third, in the time-period cross-sectional study, we did not account for potential confounding variables such as family income and parental education. Our comprehensive large-scale epidemiological study identified many previously unreported associations between SOB use and pediatric diseases. Although these findings may be specific to Hangzhou’s population and the environment, they underscore the importance of seasonal and sex-specific factors in pediatric health. We hope that our study will inspire further research into the relationship between the environmental factors of birth and common pediatric disease risk. Abbreviations ADHD: attention deficit hyperactivity disorder; G6PD deficiency: Glucose-6-phosphate dehydrogenase deficiency; SOB: season of birth; PR: prevalence ratio; UVB radiation: ultraviolet b radiation Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board/Ethics Committee of the Children’s Hospital, Zhejiang University School of Medicine (2018-IRB-046), and performed in accordance with the Declaration of Helsinki. Written informed consent was waived by the Institutional Review Board/Ethics Committee of the Children’s Hospital, Zhejiang University School of Medicine, since the utilization of anonymized retrospective data does not require patient consent under local legislation. Clinical trial number Not applicable Consent for publication All authors of this manuscript have read and approved the final version. We confirm that the content has not been published elsewhere and agree to its submission to BMC Pediatrics . Data availability statement Deidentified statistic data will be available to researchers who provide a methodologically sound proposal. The full results data can be found at http://pedmap.nbscn.org/birth.html. Competing interests All the authors declare that no competing interests exist. Funding This study is supported by the National Natural Science Foundation of China (NO. 81871456) and the Central Guiding Fund for Local Science and Technology Development Projects (NO. 2023ZY1058). Authorship contribution Yuqing Feng: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Qiang Shu: Writing – review & editing, Resources, Supervision. Haomin Li: Writing – review & editing, Methodology, Investigation, Formal analysis, Data curation, Conceptualization, Supervision, Project administration. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. References Vaiserman AM: Early-life nutritional programming of longevity . Journal of Developmental Origins of Health and Disease 2014, 5 (5):325-338. Vaiserman A: Season-of-birth phenomenon in health and longevity: epidemiologic evidence and mechanistic considerations . Journal of Developmental Origins of Health and Disease 2020, 12 (6):849-858. L J Murray, D P O'Reilly, N Betts, C C Patterson, G Davey Smith, . AEE: Season and Outdoor Ambient Temperature: Effects on Birth Weight . Obstet Gynecol 2000, 96 (5):689-695. Susanto NH, Vicendese D, Salim A, Lowe AJ, Dharmage SC, Tham R, Lodge C, Garden F, Allen K, Svanes C et al : Effect of season of birth on cord blood IgE and IgE at birth: A systematic review and meta-analysis . Environmental Research 2017, 157 :198-205. Lippi G, Salvagno GL, Montagnana M, Danese E, Guidi GC: Birth season predicts the values of red blood cell distribution width (RDW) in adulthood . Clin Chem Lab Med 2016, 54 (4):667-671. Linger Endalifer M, Diress G, Linger Endalifer B, Wagaye B, Almaw H: Does birth season correlate with childhood stunting? An input for astrological nutrition . BMC Pediatr 2022, 22 (1):306. Almqvist C, Ekberg S, Rhedin S, Fang F, Fall T, Lundholm C: Season of birth, childhood asthma and allergy in a nationwide cohort-Mediation through lower respiratory infections . Clin Exp Allergy 2020, 50 (2):222-230. Tanaka K, Matsui T, Sato A, Sasaki K, Nakata J, Nakagawa T, Sugiura S, Kando N, Nishiyama T, Kojima S et al : The relationship between the season of birth and early-onset food allergies in children . Pediatr Allergy Immunol 2015, 26 (7):607-613. Lee BK, Gross R, Francis RW, Karlsson H, Schendel DE, Sourander A, Reichenberg A, Parner ET, Hornig M, Yaniv A et al : Birth seasonality and risk of autism spectrum disorder . Eur J Epidemiol 2019, 34 (8):785-792. Coury SM, Lombroso A, Avila-Quintero VJ, Taylor JH, Flores JM, Szejko N, Bloch MH: Systematic review and meta-analysis: Season of birth and schizophrenia risk . Schizophr Res 2023, 252 :244-252. Zhang C, Brook JS, Leukefeld CG, Rosa M, Brook DW: Season of birth: A predictor of ADHD symptoms in early midlife . Psychiatry Res 2018, 267 :243-248. Sendrasoa FA, Ratovonjanahary VT, Razanakoto NH, Rakotoarisaona MF, Raharolahy O, Andrianarison M, Ranaivo IM, Mbotinirina VE, Sata M, Ramarozatovo LS et al : Birth Month and Prevalence of Atopic Dermatitis in Children Under 3 Years in Antananarivo, Madagascar . J Asthma Allergy 2020, 13 :265-268. Mao YJ, Sun L, Xie JG, Yau KK: Epidemiological features and spatio-temporal clusters of hand-foot-mouth disease at town level in Fuyang, Anhui Province, China (2008-2013) . Epidemiol Infect 2016, 144 (15):3184-3197. Weeke ER: Epidemiology of allergic diseases in children . Rhinology Supplement 1992, 13 :5-12. Cordova-Palomera A, Calati R, Arias B, Ibanez MI, Moya J, Ortet G, Crespo-Facorro B, Fananas L: Season of birth and subclinical psychosis: systematic review and meta-analysis of new and existing data . Psychiatry Res 2015, 225 (3):227-235. Hsu CW, Tseng PT, Tu YK, Lin PY, Hung CF, Liang CS, Hsieh YY, Yang YH, Wang LJ, Kao HY: Month of birth and mental disorders: A population-based study and validation using global meta-analysis . Acta Psychiatr Scand 2021, 144 (2):153-167. Chin-Hon J, Davenport L, Huang J, Akerman M, Hindenburg A: Safety and efficacy of oral anticoagulants in extreme weights . Thromb Res 2023, 231 :1-6. Thysen AH, Rasmussen MA, Kreiner-Møller E, Larsen JM, Følsgaard NV, Bønnelykke K, Stokholm J, Bisgaard H, Brix S: Season of birth shapes neonatal immune function . Journal of Allergy and Clinical Immunology 2016, 137 (4):1238-1246.e1213. Aminzadeh M, Chomeili B, Riahi K, Dehdashtian M, Cheraghian B, Valavi E: Effect of temperature changes on the occurrence of congenital hypothyroidism . J Med Screen 2010, 17 (3):121-124. Haghighi M, Wright C, Ayer J, Urban M, Pham M, Boeckmann M, Areal A, Wernecke B, Swift C, Robinson M et al : Impacts of High Environmental Temperatures on Congenital Anomalies: A Systematic Review . International Journal of Environmental Research and Public Health 2021, 18 (9). Lippi G, Bonelli P, Buonocore R, R A: Birth season and vitamin D concentration in adulthood . Ann Transl Med 2015, 3 (16):231. Babić Leko M, Jureško I, Rozić I, Pleić N, Gunjača I, Zemunik T: Vitamin D and the Thyroid: A Critical Review of the Current Evidence . International Journal of Molecular Sciences 2023, 24 (4). Ramachandran V, Edwards CF, Bichianu DC: Inguinal Hernia in Premature Infants . NeoReviews 2020, 21 (6):e392-e403. Hemati Z, Keikha M, Riahi R, Daniali SS, Goudarzi M, Kelishadi R: A systematic review on the association of month and season of birth with future anthropometric measures . Pediatric Research 2020, 89 (1):31-45. Zendejas B, Ramirez T, Jones T, Kuchena A, Ali SM, Hernandez-Irizarry R, Lohse CM, Farley DR: Incidence of inguinal hernia repairs in Olmsted County, MN: a population-based study . Ann Surg 2013, 257 (3):520-526. Fitzgibbons RJ, Jr., Forse RA: Clinical practice. Groin hernias in adults . N Engl J Med 2015, 372 (8):756-763. Domingo GJ, Advani N, Satyagraha AW, Sibley CH, Rowley E, Kalnoky M, Cohen J, Parker M, Kelley M: Addressing the gender-knowledge gap in glucose-6-phosphate dehydrogenase deficiency: challenges and opportunities . Int Health 2019, 11 (1):7-14. Beutler E, Yeh M, Fairbanks VF: The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6PD-deficiency as a marker . Proc Natl Acad Sci USA 1962, 48 :9–16. Li H, Ch'ih Y, Li M, Luo Y, Liu H, Xu J, Song W, Ma Q, Shao Z: Newborn screening for G6PD deficiency in HeFei, FuYang and AnQing, China: Prevalence, cut-off value, variant spectrum . J Med Biochem 2024, 43 (1):86-96. Jiang Z, Wang M, Tang L, Li XL, Li CR, Cheng XR: [Screening results and genetic features of glucose-6-phosphate dehydrogenase deficiency in 54 025 preterm infants in Chengdu, China] . Zhongguo Dang Dai Er Ke Za Zhi 2021, 23 (5):482-487. Rau A, Silva GS, Margolis DJ, Chiesa Fuxench ZC: Adult and infantile seborrheic dermatitis: update on current state of evidence and potential research frontiers . Int J Dermatol 2024, 63 (11):1495-1502. Nagata R, Nagano H, Ogishima D, Nakamura Y, Hiruma M, Sugita T: Transmission of the major skin microbiota, Malassezia, from mother to neonate . Pediatrics International 2012, 54 (3):350-355. Sunenshine PJ, Schwartz RA, Janniger CK, Schwartz RA: Tinea versicolor . International Journal of Dermatology 1998, 37 :648-655. Faergemann J: Management of Seborrheic Dermatitis and Pityriasis Versicolor . Am J Clin Dermatol 2000, 1 (2):75-80. Borda LJ, Perper M, Keri JE: Treatment of seborrheic dermatitis: a comprehensive review . J Dermatolog Treat 2019, 30 (2):158-169. Additional Declarations No competing interests reported. Supplementary Files Supplementaryfile.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 22 Oct, 2025 Reviewers agreed at journal 08 Sep, 2025 Reviewers invited by journal 28 Aug, 2025 Editor invited by journal 05 Aug, 2025 Editor assigned by journal 04 Aug, 2025 Submission checks completed at journal 04 Aug, 2025 First submitted to journal 25 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7212492","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":509391877,"identity":"96ff0b16-dc06-413d-ac7a-ca8a55cc7ae8","order_by":0,"name":"Yuqing Feng","email":"","orcid":"","institution":"Zhejiang University School of Medicine, National Clinical Research Centre for Child Health","correspondingAuthor":false,"prefix":"","firstName":"Yuqing","middleName":"","lastName":"Feng","suffix":""},{"id":509391878,"identity":"83018993-c10b-4acb-91c8-6ff73343f3dd","order_by":1,"name":"Qiang Shu","email":"","orcid":"","institution":"Zhejiang University School of Medicine, National Clinical Research Centre for Child Health","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Shu","suffix":""},{"id":509391879,"identity":"f5407a55-4895-4d18-93c0-48404f103756","order_by":2,"name":"Haomin Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApklEQVRIiWNgGAWjYBACAwbmhgMfGNggbCK1MDYcnEGyFmYeGJsoYC52sPGwzR++xAb25m0SDDV3CGuxnJ3YcDiHhy2xgedYmQTDsWdEOOw2SIsEUItEjpkEY8NhIrVYGAC1yL8hRQtDAsgWHhK0HOw5wGbcxpNWbJFwjCgtyYc//PhzTLaf/fDGGx9qiNACBccgkZlAtAYGhhoS1I6CUTAKRsGIAwDA7Dq8iGhC0AAAAABJRU5ErkJggg==","orcid":"","institution":"Zhejiang University School of Medicine, National Clinical Research Centre for Child Health","correspondingAuthor":true,"prefix":"","firstName":"Haomin","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-07-25 09:08:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7212492/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7212492/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90803854,"identity":"ed06345a-923f-4150-b9c7-c3801e72589d","added_by":"auto","created_at":"2025-09-08 10:37:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1407875,"visible":true,"origin":"","legend":"\u003cp\u003eThe flowchart for selecting the pediatric diseases significant associated with SOBs in children\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7212492/v1/39c31c1f9654e3de75053695.png"},{"id":90803859,"identity":"7f6feb7e-bf31-48d4-a826-bfff53536d7b","added_by":"auto","created_at":"2025-09-08 10:37:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4096681,"visible":true,"origin":"","legend":"\u003cp\u003e(a) A Manhattan plot depicting all SOB–disease associations organized by their ICD-10 (x-axis). The orange points representdiseases with ORs\u0026gt;1.2 or ORs\u0026lt;0.8 in the logistic regression model. The plot labeled35 diseases with p values\u0026lt; 1e-50.\u003cstrong\u003e \u003c/strong\u003e(b) Hierarchically clustered heatmap of ORs (OR\u0026gt;1.2 or OR\u0026lt;0.8) between diseases and SOBs. The number of ORs indicated significant associations between diseases and SOBs. Red indicates a positive association, and green indicates anegative association. Adeeper color indicates a stronger association.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7212492/v1/57279db6007a5d0398465de6.png"},{"id":90803855,"identity":"ae650fce-86e7-45aa-9558-484401fd7d90","added_by":"auto","created_at":"2025-09-08 10:37:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1027482,"visible":true,"origin":"","legend":"\u003cp\u003eThe quadrant analysis diagram of the distribution of the diseases with substantial associations (p values \u0026lt;0.05 in all tests and ORs\u0026gt;1.5 or ORs\u0026lt;0.5) in different SOBs. 4 quadrants represent 4 SOBs: the first quadrant represents summer, the second quadrant represents spring, the third quadrant represents autumn, and the fourth quadrant represents winter. The size of the disease represents the number of patients,and the color of the disease represents the type of disease.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7212492/v1/0b8ab0fa08870fd45fbc5c72.png"},{"id":90803857,"identity":"6d76d1de-87de-451e-8a72-76850e5461f2","added_by":"auto","created_at":"2025-09-08 10:37:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1425776,"visible":true,"origin":"","legend":"\u003cp\u003e(a) The prevalence and OR of novel and reported SOB-associated pediatric diseases. The plot labeled the associations with a prevalence \u0026gt;0.001 and OR\u0026gt;1.2 or OR\u0026lt;0.8. 6 outliers with obviously high ORs and high prevalence rates were excluded from the plot (high ORs: seborrheic dermatitis in infants-autumn births; high prevalences: acute upper respiratory tract infection-summer births;acute upper respiratory tract infection-autumn births; acute upper respiratory tract infection-winter births;bronchitis-summer births; and bronchitis-autumn births). (b) The number of reported and novel associated diseases (OR\u0026gt;1.5 or OR\u0026lt;0.5) in different types of diseases.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-7212492/v1/f966a29f9b37f70fc275ff56.png"},{"id":90806153,"identity":"79045a10-7784-4785-9664-62ced77eb3f6","added_by":"auto","created_at":"2025-09-08 11:01:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10577470,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7212492/v1/91e2de1b-c826-419a-b1c6-1c37f25e66b9.pdf"},{"id":90803856,"identity":"dbf6060b-e6a9-40bf-a7dd-d39743a6dab1","added_by":"auto","created_at":"2025-09-08 10:37:44","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":365604,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-7212492/v1/d4d8a43266a26a4830d7a3d5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Systematic Exploration of Birth Season-Associated Pediatric Diseases in Hangzhou, China: A Retrospective Observational Study","fulltext":[{"header":"1. Background","content":"\u003cp\u003eSeasons of birth (SOBs) influence childhood and lifelong health by acting as proxies for prenatal and early postnatal environmental exposures [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Seasonal variations in temperature, humidity, pollen levels, ultraviolet radiation intensity, and air pollution during gestation and infancy may impact developmental pathways and physiological outcomes [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, understanding the epidemiological associations between SOBs and common pediatric diseases is crucial for developing targeted strategies.\u003c/p\u003e\u003cp\u003ePrevious studies have revealed associations between SOBs and various pediatric diseases. For example, children born in the winter have a 16% greater risk of stunting than do those born in the spring and are more susceptible to asthma between the ages of 2 and 6 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Similarly, autumn and winter births are associated with an increased risk of early-onset food allergies, particularly to hen eggs, cow milk, and wheat [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], as well as a greater likelihood of autism spectrum disorder [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Other diseases, such as schizophrenia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], attention deficit/hyperactivity disorder (ADHD) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], atopic dermatitis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and hand-foot-mouth disease [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], have also shown significant seasonal associations. Collectively, these findings underscore the profound impact of SOB on health outcomes, suggesting that birth timing may shape a child's health trajectory.\u003c/p\u003e\u003cp\u003eHowever, previous studies have often focused on a narrow range of diseases, such as allergies, subclinical psychosis, and mental disorders [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Thus, this study aimed to complete a comprehensive, large-scale epidemiological study of SOB associations with a wide range of pediatric diseases, using data from millions of pediatric outpatient visits accumulated over time.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003ch3\u003e2.1 Data and Population\u003c/h3\u003e\n\u003cp\u003eData from\u0026nbsp;pediatric outpatient visits, including birth date, gender, visit time, and diagnosis, were collected from a tertiary children\u0026rsquo;s hospital with four branches in Hangzhou, Zhejiang Province. Diagnoses for each pediatric outpatient visit were recorded via the International Classification of Diseases, version 10 (ICD-10) codes.\u0026nbsp;Each ICD code had a corresponding\u0026nbsp;outcome\u0026mdash;a\u0026nbsp;binary variable. There\u0026nbsp;are\u0026nbsp;two values of outcome:\u0026nbsp;patients\u0026nbsp;with disease often\u0026nbsp;have an\u0026nbsp;outcome equal to 1, and\u0026nbsp;those\u0026nbsp;without disease often\u0026nbsp;have an\u0026nbsp;outcome equal to 0.\u003c/p\u003e\n\u003cp\u003eThis study included 10,167,101 pediatric outpatient visits (age\u0026lt;18) recorded from 2014-2021, representing 3,480,838\u0026nbsp;unique children (57.01% boys) and 7,971 distinct diagnoses. The demographic distribution of the study population\u0026nbsp;is shown in supplemental Table S1. SOBs were constructed from the seasonal distribution of Hangzhou: spring (March-May), summer (June-August), autumn (September-November), and winter (December-February). The distribution of SOBs\u0026nbsp;was slightly uneven, with more children born in autumn (26.94%, n=938,947) and fewer born in spring (23.00%, n=800,700).\u003c/p\u003e\n\u003ch3\u003e2.2 Analysis\u003c/h3\u003e\n\u003cp\u003eFig. 1\u0026nbsp;illustrates the flowchart applied to identify these associations. We employed odds ratios (ORs), 95% confidence intervals (95% CIs), and p-values from chi-square test, Bonferroni correction tests, and logistic regression models to evaluate these associations with the primary exposure\u0026nbsp;to\u0026nbsp;SOBs\u0026nbsp;[17].\u003c/p\u003e\n\u003cp\u003eThe statistical workflow was as follows:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eData filtering:\u003cul start=\"50\"\u003e\n \u003cli\u003eDiseases with more than 100 patients were included to ensure statistical power.\u003c/li\u003e\n \u003cli\u003eChi-square test with Bonferroni correction: identified diseases with significant variation across SOBs.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eConfounder control:\u003cul start=\"12\"\u003e\n \u003cli\u003eWe excluded 12 neonatal diseases (ICD-10: P00-P96) and 8 health service-related diseases (ICD-10: Z00-Z99) to avoid confounding by birth season, visit season and routine medical checkup bias.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eLogistic regression:\u003col class=\"decimal_type\" start=\"50\"\u003e\n \u003cli\u003eMultiple logistic regression models with SOBs adjusted for Age, Visit Season, and Sex.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eUltimately, diseases\u0026nbsp;that passed all tests in the statistical workflow (p-values\u0026lt;0.05) were deemed to have significant associations with SOBs.\u0026nbsp;The criteria for substantial associations between diseases and SOBs were as follows:\u003c/p\u003e\n\u003cul class=\"decimal_type\" start=\"50\"\u003e\n \u003cli\u003eP-values\u0026lt;0.05 in all tests (p-value\u0026lt;3.58e‒05 in Bonferroni correction)\u003c/li\u003e\n \u003cli\u003eOR\u0026gt;1.5 (positive) or OR\u0026lt;0.5 (negative)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eTo assess seasonal disease\u0026nbsp;risk, we calculated the prevalence ratio (PR) to evaluate the effects of all 4 SOBs on diseases with substantial associations:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cimg src=\"data:image/png;base64,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\" width=\"322\" height=\"45\"\u003e\u003c/p\u003e\n\u003cp\u003ewhere \u0026nbsp; represents the prevalence of the disease in the aim SOB. \u0026nbsp; represents the prevalence of the disease in the other 3 SOBs. PR was the maximum value for each disease in the 4 SOBs. We also explored the relationship between PR and the mean age of patients with each disease. A higher PR indicates a greater risk of disease in the target SOB than in other SOBs.\u003c/p\u003e\n\u003cp\u003eOur analysis also conducted stratified analyses to evaluate disease associations in boys and girls separately and calculated the mean age for each disease. All analyses were performed in R (v4.3.3).\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eIn this study, 1,396 diseases with sufficient patients (with more than 100 patients) were categorized into 21 groups on the basis of their ICD-10 codes (supplemental Table S2). We described the distribution of patient visits (supplemental Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). There was a sex disparity in patient visits for different types of diseases.\u003c/p\u003e\u003cp\u003eWe constructed a Manhattan plot depicting the significance of associations between SOBs and 1,396 diseases, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e(a). A total of 179 diseases were significantly associated with SOBs (including 20 types of diseases), resulting in 360 specific associations across different SOBs in the whole study population. The details of these diseases and associations are provided at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://pedmap.nbscn.org/birth.html\u003c/span\u003e\u003cspan address=\"http://pedmap.nbscn.org/birth.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo enhance the clarity of the figure, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e(b) shows the heatmap of partially significant associations (using the complete linkage clustering method), with ORs\u0026thinsp;\u0026gt;\u0026thinsp;1.2 or ORs\u0026thinsp;\u0026lt;\u0026thinsp;0.8. In Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e(b), diseases were grouped into five distinct clusters:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eLow-risk cluster for autumn: Diseases with lower risk in the autumn birth cohort typically also had low risk in the winter (or summer) birth cohort.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eHigh-risk cluster for autumn: 13 diseases that were significantly positively associated with only the autumn birth cohort.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eHigh risks for both summer and autumn: Diseases with high risks in both the summer and autumn birth cohorts, with the autumn birth cohort showing significantly higher risks.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eHigh-risk cluster for autumn and winter: Diseases with higher risks in both the autumn and winter birth cohorts, with the autumn birth cohort showing slightly higher risk.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eHigh-risk cluster for summer, autumn, and winter: Diseases with high prevalence across all SOBs (except spring).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eOverall, children born in autumn were associated with most pediatric diseases. Moreover, tinea versicolor (B36.000) and astigmatism (H52.200) had negative associations across summer, autumn, and winter. Additionally, digestive system diseases had the highest risk, which was typically observed in the autumn birth cohort, followed by the winter birth cohort.\u003c/p\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1 SOBs and diseases (spring was the reference group)\u003c/h2\u003e\u003cp\u003eAmong the 360 significant associations, 38 were classified as substantial, involving 29 diseases. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the substantial associations (OR\u0026thinsp;\u0026gt;\u0026thinsp;1.5 and OR\u0026thinsp;\u0026lt;\u0026thinsp;0.5) between the SOBs and diseases across all patients. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, 28 diseases were positively associated with SOBs (OR\u0026thinsp;\u0026gt;\u0026thinsp;1.5), whereas tinea versicolor (B36.000) was negatively associated with autumn births (OR\u0026thinsp;\u0026lt;\u0026thinsp;0.5). Notably, all 28 positively associated diseases were diagnosed earlier in the corresponding SOBs than in whole disease cohort.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSubstantial associations between SOB and diseases in all patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOB\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eICD-10\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMean Age\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMean Age*\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCounts\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCounts*\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eOR (95%CI)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eSignificant positively associated diseases\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eL21.100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e144\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.38(1.42,4.00)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eG71.200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e248\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" 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colname=\"c2\"\u003e\u003cp\u003eK40.314\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,984\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.72(1.51,1.96)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eR68.101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3,218\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11,612\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.71(1.62,1.81)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eQ17.302\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e436\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,511\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.68(1.45,1.95)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eJ21.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e608\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.67(1.31,2.13)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM16.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17,744\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e65,041\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.60(1.57,1.64)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eS73.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e362\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,168\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.59(1.35,1.87)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eQ65.801\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2,164\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7,754\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.53(1.44,1.63)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eQ65.200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e186\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e581\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.52(1.21,1.92)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eE71.302\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e292\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e960\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.50(1.26,1.80)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eK40.903\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e160\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e465\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.23(1.68,2.97)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eK44.901\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e164\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e425\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.87(1.43,2.44)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eK40.309\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e115\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e354\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.68(1.24,2.27)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eK40.314\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e631\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,984\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.61(1.41,1.83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eK40.306\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e102\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e321\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.60(1.16,2.21)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eK40.312\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e231\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e732\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.60(1.30,1.99)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eE02.x00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e210\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e619\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.52(1.22,1.90)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eE03.100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9,208\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25,171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.51(1.46,1.56)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eSignificant negatively associated diseases\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB36.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e656\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2,835\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.34(0.30,0.38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eNote: Spring was the SOB set as the reference in the analysis. Mean Age was the mean age of patients with the disease who were born in a season at the first visit; Mean Age* was the mean age of patients with the disease at the first visit; Counts was the number of patients who had the disease and were born in a season; Counts* was the number of patients who had the disease.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\u003ch2\u003e3.1.1 Born in Spring\u003c/h2\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, autumn newborns had a 66% lower risk of tinea versicolor (B36.000) than did spring newborns (OR\u0026thinsp;=\u0026thinsp;0.34, 95% CI: 0.30, 0.38). Similarly, summer-born and winter-born children had 42% (OR\u0026thinsp;=\u0026thinsp;0.58, 95% CI: 0.53, 0.64 for summer births) and 41% (OR\u0026thinsp;=\u0026thinsp;0.59, 95% CI:0.54, 0.65 for winter births) lower risks, respectively, although these associations did not meet the threshold for substantial association. Notably, tinea versicolor was the only disease in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e that had a substantial negative association with all SOBs, with spring births used as the reference.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\u003ch2\u003e3.1.2 Born in Summer\u003c/h2\u003e\u003cp\u003eCompared with autumn and winter, being born in summer was positively associated with the fewest diseases. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, seborrhoeic infantile dermatitis (L21.100), congenital myopathy (G71.200), G6PD deficiency (E74.002), acute bronchiolitis (J21.900) and jaundice (R17.x00) were strongly associated with children born in the summer. Notably, the greatest OR among these diseases occurred between seborrhoeic infantile dermatitis (L21.100) and children born in summer (OR\u0026thinsp;=\u0026thinsp;2.38, 95% CI: 1.42, 4.00), although only 144 patients were diagnosed with this disease (29.17% were born in summer). In addition, summer environmental exposure at infancy poses a significant risk for all diseases, except congenital myopathy (G71.200), for which the mean age of these patients is close to 0 years.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003e3.1.3 Born in Autumn\u003c/h2\u003e\u003cp\u003eIn contrast to summer births, autumn births were associated with the highest number of positively associated diseases, many of which were related to the digestive system. These included sliding inguinal hernia (K40.903), umbilical hernia (K42.900), incarcerated inguinal sliding hernia (K40.309), unilateral incarcerated indirect inguinal hernia (K40.306), incarcerated inguinal hernia (K40.312), and incarcerated indirect inguinal hernia (K40.314). Fortunately, most of them had relatively few patients and a relatively high mean age. However, umbilical hernia (K42.900) stood out as a disease of concern, with a relatively younger mean age (Mean Age\u0026thinsp;=\u0026thinsp;0.70) and a greater number of affected infants (Counts\u0026thinsp;=\u0026thinsp;2,235, Counts* = 7,920). Similar to summer-associated diseases, the greatest OR was observed between seborrhoeic infantile dermatitis (L21.100) and children born in autumn (OR\u0026thinsp;=\u0026thinsp;4.03, 95% CI: 2.42, 6.69). Hip-joint disease (M16.900) was another disease significantly positively associated with autumn births, with the highest number of affected patients (Counts\u0026thinsp;=\u0026thinsp;17,744, Counts*=65,041).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e3.1.4 Born in Winter\u003c/h2\u003e\u003cp\u003e8 diseases were substantial significant positive associated with winter-born children. Among these diseases, many digestive diseases associated with autumn births, including sliding inguinal hernia (K40.903), incarcerated inguinal sliding hernia (K40.309), incarcerated indirect inguinal hernia (K40.314), unilateral incarcerated indirect inguinal hernia (K40.306), and incarcerated inguinal hernia (K40.312), were also positively associated with winter births. Among these, sliding inguinal hernia (K40.903) had the greatest OR (OR\u0026thinsp;=\u0026thinsp;2.23, 95% CI: 1.68, 2.97). Hiatus hernia (K44.901) was the only digestive disease significantly positively associated with winter-born children (OR\u0026thinsp;=\u0026thinsp;1.87, 95% CI: 1.43, 2.44). In addition to digestive diseases, endocrine, nutritional, and metabolic diseases had higher risks for winter-born children, with congenital hypothyroidism (E03.100) affecting more patients (Counts\u0026thinsp;=\u0026thinsp;9,208, Counts*=25,171).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Seasonal Disease Risk Patterns\u003c/h2\u003e\u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the seasonal distribution of the 29 substantially associated diseases (OR\u0026thinsp;\u0026gt;\u0026thinsp;1.5 or OR\u0026thinsp;\u0026lt;\u0026thinsp;0.5) with the maximum PR. Notably, spring births consistently demonstrated the safest population, with only tinea versicolor (B36.000) exhibiting significantly high risk (PR\u0026thinsp;=\u0026thinsp;2.25) in this SOB. In contrast, autumn and winter births presented greater disease burdens, with 9 and 13 high-risk diseases, respectively. Risks for winter-born children were predominantly driven by hernias (PR range was 1.38\u0026ndash;1.87; the Count range was 102\u0026ndash;2,132 across 7 types) and congenital hypothyroidism (PR\u0026thinsp;=\u0026thinsp;1.71, Counts\u0026thinsp;=\u0026thinsp;9,208), and the risks of these diseases in winter births were obviously greater than those in children born in other SOBs. In the susceptible population, jaundice was the disease with the lowest mean age (Mean Age\u0026thinsp;=\u0026thinsp;0.15 in summer births), and congenital hypothyroidism was the disease with the greatest number of patients (Counts\u0026thinsp;=\u0026thinsp;10,359 in winter births). In general, each SOB showed distinct high-priority diseases, namely, tinea versicolor (spring), jaundice (summer), hip joint disease (autumn), and congenital hypothyroidism (winter), all characterized by high prevalence (higher PR and more patients) and early onset (mean age at diagnosis below 2 years old).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Novel associations and reported associations\u003c/h2\u003e\u003cp\u003eTo identify novel associations, we conducted a search on PubMed via the keywords \u0026ldquo;birth season\u0026rdquo;, \u0026ldquo;season of birth\u0026rdquo;, and the names of SOB-associated diseases. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e compares the significant positive associations identified in our study with those reported in previous studies (the references were list in Table S3). As shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, 33 diseases‒SOB associations have been previously reported in studies, with 19 consistent with our findings and 14 showing variations.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of significant positive associations in both this study and previous studies\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICD-10\u003c/p\u003e\u003cp\u003e(In this study)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSOB with highest risk\u003c/p\u003e\u003cp\u003e(In this study)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDiseases\u003c/p\u003e\u003cp\u003e(In previous studies)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSOB with highest risk\u003c/p\u003e\u003cp\u003e(In previous studies)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eConsistent Association\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC95.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAcute leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE02.x00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSubclinical hypothyroidism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE03.100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCongenital hypothyroidism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF90.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eADHD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eG71.200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIdiopathic inflammatory myopathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAugust\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eH60.501\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAtopic dermatitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJ18.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBronchiolitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eK40.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCongenital inguinal hernia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL20.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAtopic dermatitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL30.902\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAtopic dermatitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eM16.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHip joint development and morphology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eM98000/3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAcute leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQ24.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCongenital heart defects\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQ65.200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCongenital hip dislocation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQ65.801\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDevelopmental dysplasia of the hip\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQ74.102\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNewborn hip dysplasia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR32.x01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMonosymptomatic nocturnal enuresis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eS73.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNewborn hip dysplasia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eS73.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDevelopmental dysplasia of the hip\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eInconsistent Association\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB08.401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHand, foot, and mouth disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eApril-July\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE03.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAutoimmune hypothyroidism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE25.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNewborn congenital adrenal hyperplasia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE46.x00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSevere acute malnutrition\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePostharvest season and immediate pre-planting season\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE80.604\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh total serum bilirubin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOctober-March\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF80.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSpecific speech articulation disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOctober\u0026ndash;December\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF81.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLearning disabilities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eJanuary-March\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJ21.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBronchiolitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJ45.900\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAsthma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eK52.915\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCrohn\u0026rsquo;s disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSpring\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUlcerative colitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eK52.916\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRotavirus diarrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSummer\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eM16.301\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDevelopmental dysplasia of the hip\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSeptember-January\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR17.x00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAutumn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTotal serum bilirubin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOctober-March\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eR94.600\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGraves\u0026rsquo; hyperthyroidism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMales in Winter and females in Spring and Autumn or none\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHashimoto\u0026rsquo;s hyperthyroidism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWinter\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSeveral diseases from the previous literature aligned with our results, including subclinical hypothyroidism (E02.x00), congenital hypothyroidism (E03.100), congenital myopathy (G71.200), external ear eczema (H60.501), hip-joint disease (M16.900) and subluxation of the hip (S73.001). On the other hand, some diseases associated with SOBs, such as hyperbilirubinemia (E80.604), acute bronchiolitis (J21.900), jaundice (R17.x00) and dysplastic unilateral coxarthrosis (M16.301), presented divergent results in our study. These discrepancies are not unexpected, as seasonal variations can differ between regions due to different local climate patterns.\u003c/p\u003e\u003cp\u003eIn addition to the reported associations, we identified 146 diseases with no previously documented associations with SOBs in previous studies. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e(a) shows the distributions of the prevalence rates and ORs of these diseases, many of which had relatively low prevalence rates, or the magnitude of the effect was not large enough to have drawn attention in previous studies. However, some diseases, such as seborrhoeic infantile dermatitis (L21.100), disorders of fatty-acid metabolism (E71.300), G6PD deficiency (E74.002), congenital laryngeal chondromalacia (Q31.500), and sliding inguinal hernia (K40.903), deserve more attention because of their higher ORs (ORs\u0026thinsp;\u0026gt;\u0026thinsp;2.0) and earlier onset ages. Compared with other diseases, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e(b), more novel SOB-associated diseases (OR\u0026thinsp;\u0026gt;\u0026thinsp;1.5 or OR\u0026thinsp;\u0026lt;\u0026thinsp;0.5) were diseases of the digestive system, whereas more reported SOB-associated diseases were endocrine, nutritional, and metabolic diseases. More SOB-associated diseases had modest effects (OR range: 0.8\u0026ndash;1.2) and low population prevalence (\u0026lt;\u0026thinsp;0.005).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Sex disparity\u003c/h2\u003e\u003cp\u003eSome diseases show sex-specific differences, indicating that the effects of SOB may vary by sex. In this study, some obvious sex disparities in the associations between SOBs and several diseases, such as disorders of fatty-acid metabolism (E71.300), G6PD deficiency (E74.002), inguinal hernias (K40) and seborrhoeic infantile dermatitis (L21.100), were identified.\u003c/p\u003e\u003cp\u003eDisorders of fatty-acid metabolism (E71.300) had a greater risk in autumn-born boys (OR\u0026thinsp;=\u0026thinsp;3.01) than in autumn-born girls (OR\u0026thinsp;=\u0026thinsp;1.98). Similarly, hernias (K40.306, K40.309, K40.312, K40.314, K40.903, K42.900, and K44.901) presented statistically significant differences in SOBs among boys. Autumn-born boys had increased risks of unilateral incarcerated indirect inguinal hernia (OR\u0026thinsp;=\u0026thinsp;1.74 for K40.306), incarcerated inguinal sliding hernia (OR\u0026thinsp;=\u0026thinsp;1.93 for K40.309), and sliding inguinal hernia (OR\u0026thinsp;=\u0026thinsp;2.18 for K40.903). Winter-born boys had greater risks of incarcerated inguinal sliding hernia (OR\u0026thinsp;=\u0026thinsp;1.73 for K40.309) and incarcerated inguinal hernia (OR\u0026thinsp;=\u0026thinsp;1.66 for K40.312), whereas no such trend was observed in girls.\u003c/p\u003e\u003cp\u003eFor seborrhoeic infantile dermatitis (L21.100), autumn-born girls had a significantly greater risk (OR\u0026thinsp;=\u0026thinsp;5.39) than did those born in other seasons, whereas autumn-born boys had a moderately high OR of 3.47 than did those born in other seasons. Similarly, G6PD deficiency (E74.002) was markedly more common in summer-born girls (OR\u0026thinsp;=\u0026thinsp;3.15) than in those in other seasons, whereas summer-born boys had a moderate increase in risk (OR\u0026thinsp;=\u0026thinsp;1.69).\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eComprehending early-life environmental determinants of pediatric disease is essential for advancing biomedical research. Our study systematically validated and expanded the list of diseases associated with SOBs. Overall, those born in autumn and winter were more susceptible to numerous diseases, particularly various types of hernias (K40-K44), which presented higher ORs (and PRs) and affected a greater number of patients. In contrast, spring was significantly positively associated with only tinea versicolor (B36.000). Additionally, some diseases, such as disorders of fatty-acid metabolism (E71.300), G6PD deficiency (E74.002), and seborrhoeic infantile dermatitis (L21.100), exhibit sex-specific risk variations.\u003c/p\u003e\u003cp\u003eChildren born in autumn are at increased risk for a variety of diseases, including skin diseases (e.g., L21.100) and metabolic diseases (e.g., E71.300). A plausible explanation is that autumn births may influence postnatal immune system maturation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWinter-born children presented elevated risks primarily for hernias and congenital hypothyroidism. Congenital hypothyroidism has been reported to be associated with winter births [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Its high risk may be caused by low temperatures in winter. Previous studies have shown that exposure to low temperatures in the final weeks of pregnancy can increase the risk of congenital hypothyroidism [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Additionally, insufficient sunlight exposure and UVB radiation may lead to vitamin D deficiency, adversely affecting both maternal and fetal thyroid function [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, inguinal hernias (with 56,781 patients) occurred predominantly at 1\u0026ndash;3 years of age, likely because of intra-abdominal organ development and increased abdominal pressure as children begin to walk. High weight may exacerbate this risk [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A previous systematic review also revealed that individuals born in cold seasons had higher body mass indexes (BMIs) and weights in childhood, potentially explaining the increased risk of inguinal hernias in toddlers during autumn and winter [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdditionally, the risk of inguinal hernias in SOBs also varies by sex, with boys demonstrating stronger SOB associations than girls do\u0026mdash;a pattern inconsistent with established epidemiological trends [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. One explanation is the anatomical distinctions in the inguinal region: boys have wider and thinner inguinal canals due to the descent of the testes during embryonic development, making them more prone to intestinal protrusion and hernia formation [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eG6PD deficiency was another notable disease that also varied by sex in our study. We found that girls born in the summer had a particularly greater risk of G6PD deficiency (summer-born girls, OR\u0026thinsp;=\u0026thinsp;3.15; summer-born boys, OR\u0026thinsp;=\u0026thinsp;1.69). As an X-linked genetic trait, G6PD deficiency has lower diagnostic thresholds in males (XY) than in females (XX) [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The G6PD enzyme activity exhibited significant seasonal differences, reaching its minimum in summer due to high temperatures [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Another study suggested that the high temperature and humidity of summer can reduce G6PD enzyme activity in blood samples, increasing the risk of false positives for G6PD deficiency in summer births [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Consequently, these factors may disproportionately affect girls, as their enzyme activity thresholds are more sensitive to seasonal variations, and they are more likely to meet the cutoff for deficiency in summer births.\u003c/p\u003e\u003cp\u003eAmong the novel findings in this study, the strongest positive association was observed between infantile seborrheic dermatitis and autumn births. This disease, most common in infants under 1 year of age, peaks at approximately 3 months of age [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. A potential mechanism involves seasonal effects on the colonization of \u003cem\u003eMalassezia\u003c/em\u003e, a lipophilic commensal bacterium that colonizes human skin and reaches the adult type 30 days after birth [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Dry autumn air may promote the transformation of Malassezia from round blastospores to a mycelial form, exacerbating the disease [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. This hypothesis is supported by the young mean age of affected infants and the efficacy of antimycotic treatments in reducing \u003cem\u003eMalassezia\u003c/em\u003e levels and disease recurrence [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study has several notable strengths. First, to our knowledge, this is the first large-scale epidemiological study to comprehensively assess the risk of 1,396 common pediatric diseases associated with different SOBs in Hangzhou city. Second, we applied multiple rigorous statistical methods, including multiple testing corrections and stratified analyses by sex, to ensure robust findings. Third, we identified 146 novel and 33 previously reported SOB-associated diseases.\u003c/p\u003e\u003cp\u003eHowever, this study has several limitations. First, it is a single-center study, which means that these findings may not apply to other regions with different seasonal characteristics. Second, this study focused on pediatric diseases and omitted those that manifested in adulthood. Third, in the time-period cross-sectional study, we did not account for potential confounding variables such as family income and parental education.\u003c/p\u003e\u003cp\u003eOur comprehensive large-scale epidemiological study identified many previously unreported associations between SOB use and pediatric diseases. Although these findings may be specific to Hangzhou\u0026rsquo;s population and the environment, they underscore the importance of seasonal and sex-specific factors in pediatric health. We hope that our study will inspire further research into the relationship between the environmental factors of birth and common pediatric disease risk.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADHD: attention deficit hyperactivity disorder;\u003c/p\u003e\n\u003cp\u003eG6PD deficiency: Glucose-6-phosphate dehydrogenase deficiency;\u003c/p\u003e\n\u003cp\u003eSOB: season of birth;\u003c/p\u003e\n\u003cp\u003ePR: prevalence ratio;\u003c/p\u003e\n\u003cp\u003eUVB radiation: ultraviolet b radiation\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics approval and consent to participate\u003c/h3\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board/Ethics Committee of the Children\u0026rsquo;s Hospital, Zhejiang University School of Medicine (2018-IRB-046), and performed in accordance with the Declaration of Helsinki. Written informed consent was waived by the Institutional Review Board/Ethics Committee of the Children\u0026rsquo;s Hospital, Zhejiang University School of Medicine, since the utilization of anonymized retrospective data does not require patient consent under local legislation.\u003c/p\u003e\n\u003ch3\u003eClinical trial number\u003c/h3\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch3\u003eConsent for publication\u003c/h3\u003e\n\u003cp\u003eAll authors of this manuscript have read and approved the final version. We confirm that the content has not been published elsewhere and agree to its submission to\u0026nbsp;\u003cem\u003eBMC Pediatrics\u003c/em\u003e.\u003c/p\u003e\n\u003ch3\u003eData availability statement\u003c/h3\u003e\n\u003cp\u003eDeidentified statistic data will be available to researchers who provide a methodologically sound proposal. The full results data can be found at http://pedmap.nbscn.org/birth.html.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eCompeting interests\u003c/h3\u003e\n\u003cp\u003eAll the authors declare that no competing interests exist.\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eThis study is supported by the National Natural Science Foundation of China (NO. 81871456) and the Central Guiding Fund for Local Science and Technology Development Projects (NO. 2023ZY1058).\u003c/p\u003e\n\u003ch3\u003eAuthorship contribution\u003c/h3\u003e\n\u003cp\u003eYuqing Feng: Writing \u0026ndash; review \u0026amp; editing, Writing \u0026ndash; original draft, Visualization, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.\u003c/p\u003e\n\u003cp\u003eQiang Shu: Writing \u0026ndash; review \u0026amp; editing, Resources, Supervision.\u003c/p\u003e\n\u003cp\u003eHaomin Li: Writing \u0026ndash; review \u0026amp; editing, Methodology, Investigation, Formal analysis, Data curation, Conceptualization, Supervision, Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVaiserman AM: \u003cstrong\u003eEarly-life nutritional programming of longevity\u003c/strong\u003e. \u003cem\u003eJournal of Developmental Origins of Health and Disease \u003c/em\u003e2014, \u003cstrong\u003e5\u003c/strong\u003e(5):325-338.\u003c/li\u003e\n\u003cli\u003eVaiserman A: \u003cstrong\u003eSeason-of-birth phenomenon in health and longevity: epidemiologic evidence and mechanistic considerations\u003c/strong\u003e. \u003cem\u003eJournal of Developmental Origins of Health and Disease \u003c/em\u003e2020, \u003cstrong\u003e12\u003c/strong\u003e(6):849-858.\u003c/li\u003e\n\u003cli\u003eL J Murray, D P O\u0026apos;Reilly, N Betts, C C Patterson, G Davey Smith, . 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Therefore, this study comprehensively and systematically investigates the associations between SOBs and numerous common pediatric diseases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a retrospective observational study of 3,480,838 children (age\u0026lt;18, 2014-2021) with 10,167,101 outpatient visits recorded in Hangzhou, China. Assessing associations between 1,396 common pediatric diseases (case counts \u0026gt;100) and SOBs by chi-square test with Bonferroni correction, odds ratios (ORs) from adjusted logistic regression models (adjusted for sex, age, and visit season) and prevalence ratios (PRs, SOB vs the other 3 SOBs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 360 significant associations across 179 SOB-associated diseases (details at http://pedmap.nbscn.org/birth.html), including 146 novel diseases and 33 previously reported diseases, were identified. Spring births were only positively significant associated with tinea versicolor (PR=-0.54). The strongest positive association was observed between seborrhoeic infantile dermatitis and autumn births (OR=4.03, 95% CI 2.42 to 6.69; PR= 0.52). Additionally, the effects of SOBs on disease risk varied significantly between sexes, particularly for disorders of fatty-acid metabolism (boys: OR=3.01 vs girls: OR=1.98) and seborrhoeic infantile dermatitis (boys: OR=3.47 vs girls: OR=5.39) in autumn births, G6PD deficiency (boys: OR=1.69 vs girls: OR=3.15) in summer births, and all kinds of inguinal hernias in winter births.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis systematic investigation corroborated previous findings and identified novel associations between pediatric diseases and SOB. Children born in autumn and winter may be at greater risk for various diseases, with some diseases exhibiting notable sex disparities in their associations with SOBs. These insights highlight the importance of considering seasonal and sex-related factors in pediatric disease prevention and management strategies.\u003c/p\u003e","manuscriptTitle":"Systematic Exploration of Birth Season-Associated Pediatric Diseases in Hangzhou, China: A Retrospective Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 10:37:40","doi":"10.21203/rs.3.rs-7212492/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-10-23T00:11:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186494109426414003985995994139972722482","date":"2025-09-08T19:22:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-28T17:46:18+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-05T08:36:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-04T10:08:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-04T10:07:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-07-25T09:02:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cb0b5035-939f-49cf-88f8-733b1c938ac2","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T10:37:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-08 10:37:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7212492","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7212492","identity":"rs-7212492","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}