To the Editor,
The progression of atopic dermatitis (AD) to allergic asthma (AA) and/or allergic rhinitis (AR) is defined as Atopic march1. The reason why some children developed AD-only while others continued with Atopic march is not well-understood. Previous studies found differences in the incidence and progression patterns of allergic diseases among children of different race/ethnicities. For example, compared to White children, Black children have a higher prevalence of atopic diseases as well as greater associated morbidity and mortality2. Some studies reported that among children with AD, Black children were more prone to develop AA, whereas White children were more likely to develop AR3,4. However, prior studies on racial differences in the Atopic march have focused primarily on child genetic and environmental factors but have not considered prenatal and maternal factors, which are known to affect child’s immune system5. In this study, we sought to examine multiple early-life factors in relation to AD and the Atopic march in 1998 mother-child pairs from the Boston Birth Cohort (BBC), a long-term prospective cohort of high-risk (37.6% AD incidence), primarily urban, low-income, and racial/ethnic minority (80.9% Black and Hispanic) populations who have been historically underrepresented in atopic disease research (Figure S1).
Compared to children without AD, children who had AD (all-AD) were more likely to be Black (OR, 1.6; 95% CI: 1.1–2.4, p=0.029), male (OR, 1.3; 95% CI: 1.1–1.5, p=0.010), exclusively breastfed (OR, 1.6; 95% CI: 1.1–2.3, p=0.011), or born to mothers with obesity (OR, 1.4; 95%CI: 1.1–1.8, p=0.003) (Table 1A and Table S2–3). Similarly, being male (OR, 1.3; 95% CI: 1.0–1.6, p=0.029), exclusively breastfed (OR, 1.9; 95% CI: 1.3–3.0, p=0.003), or maternal obesity (OR, 1.4; 95% CI: 1.0–1.9, p=0.026) were the risk factors for having AD-only. Interestingly, preterm birth was observed as a protective factor against developing AD (AD-only vs. non-atopic: OR, 0.6; 95% CI: 0.4–0.8, p<0.001; All-AD vs. non-atopic: OR, 0.8; 95% CI: 0.6–1.0, p=0.03) (Table 1A). The only non-mutual risk factor between AD-only and All-AD children was race/ethnicity: while non-Hispanic black was a risk factor for All-AD (AD-only plus Atopic march), it did not show any significant difference in the AD-only children (Table 1A) compared to non-AD children. Compared to AD-only children, those who developed the Atopic march were more likely to be Hispanic (OR, 2.4; 95% CI: 1.1–5.4, p=0.036), being born to nulliparous (OR, 1.5; 95% CI: 1.1–2.1, p=0.006), preterm (OR, 1.8; 95% CI: 1.2–2.6, p=0.002), and have maternal atopy history (OR, 1.6; 95% CI: 1.2–2.3, p=0.003) (Table 1B).
Table 1. Adjusted associations between significant risk factors and the risk of Child atopic condition.
All adjusted models were compared with the Non-AD group (A) or AD-only group (B) with adjustment for the presented variables.
| AD-only (n = 399) | Atopic march (n = 352) | All AD (n = 751) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Non-AD | No. | OR [95% CI] | P Value | No. | OR [95% CI] | P Value | No. | OR [95% CI] | P Value | |
| Race/ethnicity | |||||||||||
| Non-Hispanic white | 123 | 87 | 24 | 1 [Reference] | NA | 12 | 1 [Reference] | NA | 36 | 1 [Reference] | NA |
| Non-Hispanic black | 1173 | 684 | 253 | 1.2 [0.7, 2] | 0.48 | 236 | 2.4 [1.3, 4.5] | 0.007 | 489 | 1.6 [1.1, 2.4] | 0.029 |
| Hispanic | 453 | 328 | 63 | 0.6 [0.4, 1.1] | 0.101 | 62 | 1.4 [0.7, 2.8] | 0.291 | 125 | 0.9 [0.6, 1.4] | 0.65 |
| Others | 249 | 148 | 59 | 1.3 [0.7, 2.2] | 0.391 | 42 | 2.2 [1.1, 4.4] | 0.034 | 101 | 1.6 [1.1, 2.4] | 0.029 |
| Maternal BMI | |||||||||||
| Normal | 997 | 640 | 196 | 1 [Reference] | NA | 161 | 1 [Reference] | NA | 357 | 1 [Reference] | NA |
| Overweight | 557 | 362 | 98 | 0.9 [0.7, 1.2] | 0.326 | 97 | 1 [0.7, 1.3] | 0.976 | 195 | 0.9 [0.7, 1.2] | 0.506 |
| Obesity | 444 | 245 | 105 | 1.4 [1, 1.9] | 0.026 | 94 | 1.5 [1.1, 2] | 0.011 | 199 | 1.4 [1.1, 1.8] | 0.003 |
| Parity | |||||||||||
| Multiparous | 1149 | 724 | 241 | 1 [Reference] | NA | 184 | 1 [Reference] | NA | 425 | 1 [Reference] | NA |
| Nulliparous | 849 | 523 | 158 | 0.9 [0.7, 1.2] | 0.524 | 168 | 1.4 [1.1, 1.8] | 0.012 | 326 | 1.1 [0.9, 1.3] | 0.26 |
| Child’s sex | |||||||||||
| Female | 1050 | 684 | 193 | 1 [Reference] | NA | 173 | 1 [Reference] | NA | 366 | 1 [Reference] | NA |
| Male | 948 | 563 | 206 | 1.3 [1, 1.6] | 0.029 | 179 | 1.3 [1, 1.6] | 0.056 | 385 | 1.3 [1.1, 1.5] | 0.01 |
| Last Visit Age | |||||||||||
| >=6 | 449 | 301 | 95 | 1 [Reference] | NA | 53 | 1 [Reference] | NA | 148 | 1 [Reference] | NA |
| <6 | 1549 | 946 | 304 | 1 [0.8, 1.4] | 0.809 | 299 | 0.6 [0.4, 0.8] | <0.001 | 603 | 0.8 [0.6, 1] | 0.044 |
| Preterm birth | |||||||||||
| NO | 1528 | 932 | 332 | 1 [Reference] | NA | 264 | 1 [Reference] | NA | 596 | 1 [Reference] | NA |
| YES | 470 | 315 | 67 | 0.6 [0.4, 0.8] | <0.001 | 88 | 1 [0.8, 1.3] | 0.934 | 155 | 0.8 [0.6, 1] | 0.03 |
| Feeding | |||||||||||
| Bottlefeeding | 501 | 334 | 85 | 1 [Reference] | NA | 82 | 1 [Reference] | NA | 167 | 1 [Reference] | NA |
| Both | 1333 | 822 | 269 | 1.3 [1, 1.7] | 0.086 | 242 | 1.1 [0.9, 1.5] | 0.362 | 511 | 1.2 [1, 1.5] | 0.089 |
| Breastfeeding | 164 | 91 | 45 | 1.9 [1.3, 3] | 0.003 | 28 | 1.3 [0.8, 2.1] | 0.365 | 73 | 1.6 [1.1, 2.3] | 0.011 |
| Maternal atopy history | |||||||||||
| NO | 1391 | 889 | 283 | 1 [Reference] | NA | 219 | 1 [Reference] | NA | 502 | 1 [Reference] | NA |
| YES | 607 | 358 | 116 | 1 [0.7, 1.3] | 0.803 | 133 | 1.5 [1.2, 2] | 0.001 | 249 | 1.2 [1, 1.5] | 0.063 |
| Atopic march (n = 352) | |||||
|---|---|---|---|---|---|
| Total | AD-only | No. | OR [95% CI] | p-value | |
| Race/ethnicity | |||||
| Non-Hispanic white | 36 | 24 | 12 | 1 [Reference] | NA |
| Non-Hispanic black | 489 | 253 | 236 | 2.1 [1, 4.3] | 0.057 |
| Hispanic | 125 | 63 | 62 | 2.4 [1.1, 5.4] | 0.036 |
| Others | 101 | 59 | 42 | 1.7 [0.7, 3.9] | 0.214 |
| Maternal BMI | |||||
| Normal | 357 | 196 | 161 | 1 [Reference] | NA |
| Overweight | 195 | 98 | 97 | 1.1 [0.7, 1.5] | 0.735 |
| Obesity | 199 | 105 | 94 | 1.1 [0.7, 1.5] | 0.785 |
| Parity | |||||
| Multiparous | 425 | 241 | 184 | 1 [Reference] | NA |
| Nulliparous | 326 | 158 | 168 | 1.5 [1.1, 2.1] | 0.006 |
| Child’s sex | |||||
| Female | 366 | 193 | 173 | 1 [Reference] | NA |
| Male | 385 | 206 | 179 | 1 [0.7, 1.3] | 0.98 |
| Last Visit Age | |||||
| <6 | 148 | 95 | 53 | 1 [Reference] | NA |
| >=6 | 603 | 304 | 299 | 0.5 [0.3, 0.8] | <0.001 |
| Preterm birth | |||||
| NO | 596 | 332 | 264 | 1 [Reference] | NA |
| YES | 155 | 67 | 88 | 1.8 [1.2, 2.6] | 0.002 |
| Feeding | |||||
| Bottle feeding | 167 | 85 | 82 | 1 [Reference] | NA |
| Both | 511 | 269 | 242 | 1 [0.7, 1.4] | 0.807 |
| Breast feeding | 73 | 45 | 28 | 0.7 [0.4, 1.3] | 0.301 |
| Maternal atopy history | |||||
| NO | 502 | 283 | 219 | 1 [Reference] | NA |
| YES | 249 | 116 | 133 | 1.6 [1.2, 2.3] | 0.003 |
Abbreviations: AD, atopic dermatitis; OR, odds ratio; CI, confidence interval; BMI, body mass index; NA, not applicable.
We observed that compared to Non-AD children, being male is a risk factor for All-AD (OR, 1.3; 95% CI: 1.1 −1.5, p=0.010) (Table 1A); and compared to AD-only children, preterm is a risk factor for children to develop the Atopic march (OR, 1.8; 95% CI: 1.2–2.6, p=0.002) (Table 1B). Consequently, we performed subgroup analyses of the associations between gender (male vs female) and the risk of All-AD and preterm (Yes vs No) and the risk of Atopic March. The result showed that the point estimates of the association between gender and All-AD and preterm and Atopic march were in the positive direction across strata of potential confounders (Figure 1A and 1B). A larger difference in the point estimate of the ORs for All-AD was observed across strata of race (OR within white, 2.18; 95% CI: 1.02–4.81, p=0.048), and feeding (OR within breast feeding, 2.46; 95% CI: 1.31–4.62, p=0.005) (Figure 1A). A larger difference in the point estimate of the ORs for Atopic march was observed across strata of sex (OR within male, 4.22; 95% CI: 2.45–7.30, p＜0.001), and CBIgE (OR within detectable CBIgE, 2.71; 95% CI: 1.23–5.99, p=0.013) (Figure 1B).
Figure 1. Forest Plots Summarizing the Subgroup Analyses.
Subgroup analyses of the associations between gender (male vs female) and the risk of All-AD (A) and preterm (Yes vs No) and the risk of Atopic March (B). Squares represent mean values, with whiskers indicating 95% CIs. Abbreviations: AD, atopic dermatitis; OR, odds ratio; CI, confidence interval; BMI, body mass index; CBIgE, Cord Blood total IgE.
We found that there was no statistical difference in maternal age at delivery, family income, maternal marital status, maternal education, maternal smoking during pregnancy, alcohol history, child’s birth weight, delivery type, hypertensive disorder of pregnancy, or maternal diabetes between non-atopic children, AD-only, and Atopic march children (P ≥0.05) (Table S1).
Within the subgroup of 736 children who had measured CBIgE, a test of interaction between maternal atopic history and CBIgE was statistically significant (Table S4). The mother-child pairs with CBIgE data had similar demographic characteristics as those without CBIgE data. Although neither maternal atopy history (p=0.347) nor detectable CBIgE (p=0.842) was a significant risk factor for Atopic march, we observed that the individuals who have both maternal atopy history and detectable CBIgE have a significantly increased risk of developing Atopic march (OR, 4.8; 95% CI: 1.4–18.3, p=0.017) (Table S5). We also found that the level of CBIgE was positively correlated with the children’s risk of All-AD and Atopic march, especially when their mothers have atopy history (Figure S2A–B).
In summary, in this sample of US, urban, low income, high-risk, minority children, we revealed shared and differential risk factors for AD-only and for the progression from AD to Atopic march. Our findings, if further confirmed in other independent birth cohorts with the addition of information on temporal sequence of exposures, paternal factors, and children’s BMI at different stages, raise the prospective of early risk assessment and identification of children at high-risk of Atopic march, and development of targeted interventions at the earliest developmental stage.
Supplementary Material
Acknowledgements
The authors wish to thank the study participants of the Boston Birth Cohort and the entire field team of the Boston Medical Center.
Funding information
The Boston Birth Cohort (the parent study) was supported in part by the National Institutes of Health (NIH) grants (2R01HD041702, R01HD098232, R01ES031272, R21AI154233, R01ES031521, U01 ES034983 and R21AI171059); and the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) (UT7MC45949). Dr. Xiumei Hong is supported by Hopkins Population Center NICHD R24HD042854. Dr. Luis Garza was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under R01AR074846 01 and UG3 AR079376, and the Thomas Provost, MD, Young Faculty Development Fund of Johns Hopkins Dermatology. Dr. Gaofeng Wang is support by the National Natural Science Foundation of China (82202468, 82372532), Natural Science Foundation of Guangdong Province (2023A1515012227), the Foundation of Guangzhou Municipal Science and Technology Bureau, the Basic Research Program - Basic and Applied Basic Research Project (SL2022A04J02027), High Level Introduction of Talent Research Startup Fund of Southern Medical University (Gaofeng Wang) and Nanfang Hospital Distinguished Young Cultivation Program (2022J003).This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by the US Government.
Conflict of interest statement
J.W. has received fellowship and research funding from Pfizer (paid to Johns Hopkins University) and has served as an advisor to Janssen and Sun Pharmaceuticals (Data Monitoring Committee).
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