Parental atopy and risk of atopic dermatitis in the first two years of life in the BASELINE birth cohort study

Abstract Background Atopic dermatitis (AD) has a strong genetic basis. The objective of this study was to assess the association between parental atopy and AD development by 2 years. Methods A secondary data analysis of the BASELINE Birth Cohort study was performed (n = 2183). Parental atopy was self‐reported at 2 months. Infants were examined for AD by trained health care professionals at 6, 12, and 24 months. Variables extracted from the database related to skin barrier function, early skincare, parental atopy, and AD. Statistical analysis adjusted for potential confounding variables. Results Complete data on AD status were available for 1505 children at 6, 12, and 24 months. Prevalence of AD was 18.6% at 6 months, 15.2% at 12 months, and 16.5% at 24 months. Adjusted odds ratios (95% CIs) following multivariable analysis were 1.57 (1.09–2.25) at 6 months and 1.66 (1.12–2.46) at 12 months for maternal AD; 1.90 (1.28–2.83) at 6 months and 1.85 (1.20–2.85) at 24 months for paternal AD; 1.76 (1.21–2.56) at 6 months and 1.75 (1.16–2.63) at 12 months for maternal asthma; and 1.70 (1.19–2.45) at 6 months, 1.86 (1.26–2.76) at 12 months, and 1.99 (1.34–2.97) at 24 months for paternal asthma. Parental rhinitis was only associated with AD with maternal rhinitis at 24 months (aOR (95% CI): 1.79 (1.15–2.80)). Conclusion Parental AD and asthma were associated with increased risk of objectively diagnosed AD in offspring in this contemporary cohort.


| INTRODUCTION
Atopic dermatitis (AD) affects one in five children, 1

usually starts in
the first year of life, and commonly persists into adulthood. 2 The pathophysiology of AD is complex, involving skin barrier dysfunction, 3 aberrant immune responses, 4 and environmental factors such as microbial exposure. 5 Loss of function mutations in FLG, the gene encoding filaggrin, represent the greatest genetic risk factor for development of AD. 6 Previous studies have shown differing odds ratios for AD in offspring of parents with atopic disease, although parental AD has been consistently associated with increased risk. [7][8][9][10] The Avon longitudinal study of parents and children (ALSPC) showed a strong association between parental AD and childhood AD, with an odds ratio of 1.69 (95% confidence interval 1.47-1.95) for maternal AD, 1.74 (1.44-2.09) for paternal AD, and 2.72 (2.09-3.53) for biparental AD. 7 The PARIS prospective birth cohort study showed that parental atopy (AD and/or asthma and/or rhinitis) was associated with an odds ratio of 2.31 (1.28-4.16) for severe AD. 11 The Protection Against Allergy Study in Rural Environments (PASTURE) birth cohort study showed that having one parent with atopy (AD and/or asthma and/or rhinitis) was associated with an odds ratio of 1.36 (0.84-2.20) for early transient AD, 2.15 (1.15-4.03) for early persistent AD, and 1.58 (0.83-3.03) for late AD; while having two parents with atopy was associated with an odds ratio of 2.46 (1.27-4.76) for early transient AD, 5.35 (2.52-11.36) for early persistent AD, and 2.41 (0.95-6.09) for late AD. 12 Some studies have suggested that maternal atopy is more strongly associated with AD, 10,13 while others have not identified a difference in risk between maternal or paternal atopy. 7,8 We aimed to assess the impact of maternal and paternal atopic disease on AD outcomes in offspring in early life in a large observational birth cohort study.

| Study subjects
This study was a secondary analysis of the Cork Babies After Scope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE) Birth Cohort study. 14

| Atopy and atopic dermatitis assessments
All infants had assessments at birth, 2 months, 6 months, 12 months, and 24 months involving parental questionnaires and physical assessment. Self-reported parental atopy (AD, asthma, or allergic rhinitis) was investigated by the questions • DO or DID you ever suffer from eczema (atopic dermatitis)?
• DO or DID you ever suffer from asthma?
• DO or DID you ever suffer from pollen-related rhinitis ("hayfever")?
Parental atopy was self-reported at 2 months. Parents were asked at 2 months if the infant had an "itchy rash on the face or in the folds of the arms or legs," as a screening question for AD. Experienced health care personnel diagnosed AD at 6, 12, and 24 months according to the UK Working Party diagnostic criteria. 15

| Statistical analysis
Categorical variables were described using frequency (percentage). Univariable and multivariable logistic regression models were used to investigate relationships between maternal and paternal atopic conditions, potential confounding variables and the presence of AD at 6 months, 12 months, and 24 months of age separately, and at all-time points. The potential confounders included were sex, birth weight, transepidermal water loss (TEWL) at 2 months, parent-reported "itchy rash" at 2 months, emollient bathing at 2 months, frequency of bathing at 2 months, and frequency of emollient application at 2 months. For all independent variables, the unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) are presented.
Prior to performing the multivariable logistic regression analyses, multicollinearity among the independent variables was tested using the variance inflation factor (VIF). All tests were two-sided and a p-value <.05 was considered statistically significant. Statistical analysis was performed using Stata (version 15.1, StataCorp LP, College Station, TX).

| RESULTS
A flow diagram outlining study recruitment is shown in Figure 1. Complete data on AD status were available for 1505 children at 6, 12, and 24 months. Prevalence of AD was highest at 6 months (18.6%), decreasing to 15.2% at 12 months, and increasing to 16.5% at F I G U R E 1 Flow diagram showing each stage of the BASELINE study. n, number of infants; LFU, lost to follow up; CW, consent withdrawn

| Relationship between parental atopy and AD in first 2 years of life
Parental atopic disease (either maternal or paternal or biparental history of AD and/or asthma and/or rhinitis) was associated with AD in both univariable and multivariable analysis (n = 1296). Based on the multivariable analysis, the odds of AD in the first 2 years of life were higher among infants whose mother or father or both parents had a history of atopy {adjusted OR (95% CI): 2.26 (1.75-2.91), p < .001}. Maternal atopic disease (AD and/or asthma and/or rhinitis) was also associated with AD in both univariable and multivariable analysis. Based on the multivariable analysis, the odds of AD in the first 2 years of life were higher among infants whose mothers had a history of atopy {adjusted OR (95% CI): 1.70 (1.31-2.22), p < .001}. Paternal atopic disease (AD and/or asthma and/or rhinitis) was also associated with AD in both univariable and multivariable analysis. Based on the multivariable analysis, the odds of AD in the first 2 years of life were higher among infants whose fathers had a history of atopy {adjusted OR (95% CI): 1.99 (1.51-2.61), p < .001}.
3.2 | Relationship between specific parental atopic disease and AD at 6 months At 6 months, maternal AD and asthma and paternal AD and asthma were significantly associated with AD, in both univariable and multivariable analysis (Table 1). Based on the multivariable analysis, the odds of AD at 6 months were higher among infants whose

| Relationship between specific parental atopic disease and AD at 12 months
At 12 months, maternal AD and asthma and paternal AD and asthma were significantly associated with AD, in the univariable analysis (Table 2). Paternal AD was no longer significantly associated with AD following multivariable analysis (p = .060). Based on the multivariable analysis, the odds of AD at 12 months were higher among infants whose mothers had AD {adjusted OR (95% CI): 1 Includes the variables listed and sex, birth weight, and TEWL, "itchy rash," emollient bathing, frequency of bathing, and frequency of emollient application at 2 months.

| Relationship between specific parental atopic disease and AD at 24 months
At 24 months, maternal AD, asthma and rhinitis and paternal AD and asthma were significantly associated with AD, in the univariable analysis (Table 3). Maternal AD (p = .359) and asthma (p = .216) were no longer significantly associated with AD following multivariable analysis. Based on the multivariable analysis, the odds of AD at 24 months were higher among infants whose mothers had rhinitis {adjusted OR

| DISCUSSION
This secondary data analysis of a large unselected first-born cohort showed an increased risk of AD in those who had a parental history of atopy, and specifically a maternal or paternal history of AD or asthma.
These results were consistent even after accounting for confounding factors, such as birth weight and transepidermal water loss (TEWL) at 2 months. This study showed a similar or slightly higher impact of paternal atopy on AD development, compared to maternal atopy.
Parental allergic rhinitis was not associated with AD in offspring in the  Most previous studies have used parent-reported data for diagnosis of atopy in both parents and children. [7][8][9] Very few studies have used objective assessment of AD for diagnosis in offspring.
The prevalence of AD in children has increased dramatically in recent years, 16

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.