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Early-Life Risk Factors for Occurrence of Atopic Dermatitis During the First Year

^a Department of Pediatrics and Developmental Medicine, Gunma University Graduate School of Medicine, Gunma, Japan
^b Ozawa Obstetric Clinic, Gunma, Japan

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVE. In a prospective birth cohort study, we sought to identify perinatal predictors of the occurrence of atopic dermatitis in the first year of life.

METHODS. Associations of family history, infection during pregnancy, cord blood cytokine concentrations, and skin function parameters with atopic dermatitis were analyzed. Stratum corneum hydration was measured with an impedance meter until 5 days after delivery and again at 1 month.

RESULTS. Complete data were obtained for 213 infants, including 27 diagnosed by a physician as having atopic dermatitis during their first year and 26 diagnosed as having infantile eczema during their first month. The risk of atopic dermatitis during the first year of life was related to maternal atopic dermatitis, lower concentrations of macrophage inflammatory protein-1β in cord blood, and greater skin moisture in the surface and stratum corneum of the forehead and cheek at 1 month of age but not to viral or bacterial infection during pregnancy or breastfeeding. Paternal hay fever was associated negatively with the development of atopic dermatitis. High concentrations of interleukin-5, interleukin-17, and macrophage chemotactic protein-1 and only surface moisture in the cheek were associated with greater risk of infantile eczema in the first month.

CONCLUSIONS. The association of atopic dermatitis in infancy with reduced neonatal macrophage inflammatory protein-1β levels suggests a link with immature immune responses at birth. Stratum corneum barrier disruption in atopic dermatitis may involve impairment of cutaneous adaptation to extrauterine life. The majority of risk factors had different effects on infant eczema and atopic dermatitis, indicating different causes.

Key Words: atopic dermatitis • skin physiology • cytokine • chemokine • infantile eczema

Abbreviations: AD—atopic dermatitis • IL—interleukin • TNF—tumor necrosis factor • IFN—interferon • MCP—monocyte chemotactic protein • MIP—macrophage inflammatory protein • OR—odds ratio • CI—confidence interval • Th—T helper

Atopic dermatitis (AD), a chronic inflammatory skin disease that usually occurs in the first few years of life,¹ has increased dramatically in prevalence in developed countries over the past several decades. AD and other allergic diseases seem to have multifactorial origins, arising from complex interactions between genes and the environment; however, the relative importance of genetic and prenatal environmental factors is not yet clear. AD is one of the earliest manifestations of allergic/atopic diseases in children. Furthermore, AD is considered a significant risk factor for aeroallergen sensitization at 5 years and a predictor of the subsequent development of asthma.² Asthma is a worldwide problem, and the disease's social burden and costs to public and private health care systems are substantial. Therefore, establishing early risk factors for AD may help provide intervention strategies for the primary prevention of asthma.³

Cytokines are considered important regulators of functional maturation in the developing fetal immune system. However, factors that determine the degree of immune competence at birth and during early infancy are not fully understood. Several studies have linked cytokine profiles at birth to subsequent development of allergic disorders.^4–7 Tang et al⁴ found that infants who either exhibited symptoms of atopic disease or had a positive skin test at 1 year of age produced significantly less interferon (IFN)- at birth than did infants without atopy. Macaubas et al⁵ found negative relationships of interleukin (IL)-4, IFN-, and tumor necrosis factor (TNF)- concentrations in cord blood to the risk of asthma, atopy, or both by 6 years of age. These findings suggested that some immune functions, including the capacity to secrete both T helper (Th) type 1 and 2 cytokines, are attenuated at birth in children who develop atopy subsequently. Most previous studies focused on the relationship between Th1/Th2 cytokines at birth and future development of atopic diseases. However, a few reports examined specifically links between levels of serial cytokines, which play roles in inflammation, maturation of T cells, and production and maintenance of the Th1/Th2 balance, at birth and future development of atopic diseases.

The pathogenesis of AD involves both allergic predisposition and nonallergic environmental factors. Skin barrier disruption has attracted attention as a nonallergic etiologic factor for AD, characterized by disorders of water retention and skin barrier function.⁸ One study reported that levels of ceramide, a lipid contributing to skin function, were significantly lower in lesional and nonlesional skin of subjects with AD, compared with control subjects.⁹ However, we know of no reported data concerning when in life dry skin and subsequent skin barrier disruption first become apparent in children who develop AD.

The purpose of the present prospective birth cohort study was to assess the risk of prenatal maternal factors and immunologic profiles at birth and skin functional parameters just after delivery and at 1 month of age in development of AD during the first year of life. To do this, we measured levels of 17 kinds of cytokines, including proinflammatory cytokines, Th1/Th2 distinguishing cytokines, nonspecifically acting cytokines, and chemokines, in serum from cord blood and measured stratum corneum hydration with an impedance meter until 5 days after delivery and again at 1 month.

	METHODS

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Subjects
This was a prospective cohort study examining multiple prenatal and perinatal factors in relation to child health outcomes. Participants were recruited at Ozawa Obstetric Clinic in Gunma Prefecture, where we explained the study to pregnant women and obtained informed consent at the routine clinic visit corresponding to 35 to 37 weeks of gestation. We enrolled 279 pregnant women (93.9% of eligible subjects) between June 1, 2002, and May 31, 2003. Only children born at term without significant neonatal respiratory difficulties or pathologic jaundice were included in the study, to avoid influences on infant skin physiologic features from humidification in an infant incubator or dehydration during phototherapy. These criteria excluded only 10 children.

Cord blood was collected from participants at birth. Blood was centrifuged at 3000 x g for 15 minutes, and serum was separated and stored at –30°C until cytokine measurement. Mothers were provided a self-administered questionnaire and interviewed briefly. Pregnancy and perinatal data were collected from perinatal records. The main factors taken into account were parental history of atopic disease (asthma, eczema, or hay fever), maternal age, viral infection (upper airway or gastrointestinal infection) or bacterial infection (urinary tract or vaginal infection attributable to Escherichia coli, Chlamydia spp, Gram-positive group B streptococcus, or other bacteria) during the prenatal period, gestational age, infant birth weight, and method of delivery. This study was approved by the committee of ethics at the Department of Pediatrics and Developmental Medicine, Gunma University Graduate School of Medicine.

Follow-up Examinations
In physical examinations at the 1-month checkup visit in our clinic, one of the authors noted the presence or absence of eczema on the face. At that time, physiologic skin measurements also were performed. Children were diagnosed as having infantile eczema when facial eczema was present at 1 month of age. All children were monitored for at least 1 year, for assessment of the development of atopic diseases such as AD, asthma-like illness, and food allergies. Parents were asked directly, through mail or telephone interviews, whether they had been told by a physician that their child had AD. Information on lifestyle factors and other potential risk factors, including breastfeeding history (exclusive breastfeeding, partial breastfeeding, or milk formula feeding), also was collected with a parental questionnaire.

Skin Physiologic Measurements
Stratum corneum hydration was measured on the forehead, cheek, flexor aspect of the forearm near the cubital fossa, and chest at 5 to 10 hours after delivery and then once daily until 5 days after delivery. All tests were performed in open cribs in a controlled environment, with room temperature ranging from 22°C to 24°C and humidity at 50%. Skin temperature remained stable during the examination for all newborns. Stratum corneum hydration was measured by using a moisture meter (ASA-M1; Asahi Biomed, Tokyo, Japan),¹⁰ based on capacitance and electrical conductance determined at 2 different frequencies (160 Hz and 143 kHz) with 2 concentric surface electrodes. The probe was pressed on the skin surface for 1 to 2 seconds. Each measurement was obtained twice at the same site; data were rejected when children were crying or visibly sweating. Parameters obtained were moisture content on the skin surface and moisture content in the stratum corneum.

Multiplex Cytokine Array Analysis
Multiplex cytokine array analysis was performed by using the Bio-Plex protein array system (Bio-Rad Laboratories, Hercules, CA), using Luminex-based technology.¹¹ With this assay, we quantitated cytokines simultaneously in serum from cord blood, including IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, and IL-17, IFN-, and TNF-, granulocyte/macrophage colony-stimulating factor, granulocyte colony-stimulating factor, monocyte chemotactic protein (MCP)-1, and macrophage inflammatory protein (MIP)-1β. Most standard curves ranged between 0.2 pg/mL and 3200 pg/mL. At higher and lower concentrations, standard curves became flat and lost linearity. Lower limits of detection for the assays used were 0.2 pg/mL for all cytokines studied. Samples with undetectable concentrations were assigned a value of 0.1 pg/mL (ie, halfway between 0 and the lower limit of detection for the assay).

Statistical Methods
The relationship between eczema in infancy and various maternal and perinatal risk factors was assessed by using Pearson ² tests. Differences in clinical characteristics at birth and in skin physiologic parameters between children with and without AD in the first year of life were analyzed by using Student's t tests. Because the distribution of cytokines is highly skewed, with many values below the lower limit of detection, the Mann-Whitney U test was used to compare cytokine concentrations in cord blood between children with and without AD or infantile eczema. Multivariate logistic regression models were used to determine independent effects of different factors associated with AD in this population; results are expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Subject characteristics and prenatal factors that were statistically significant in Pearson ² tests, Student's t tests, or Mann-Whitney U tests were included in the multivariate model.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Family History and Prenatal Factors
Children in this study were monitored prospectively, and questionnaire data from 213 (79%) were collected to assess the incidence of AD during the first year of life. The cumulative incidence of maternally reported, physician-diagnosed AD in the cohort was 27 cases (12.4%) among 213 children. Infant gender, method of delivery, length of gestation, birth weight, and maternal age did not differ between children with and without AD (Table 1). Exclusive breastfeeding was not related to the development of AD (Table 1). Rates of maternal bacterial or viral infection during pregnancy did not differ between the 2 groups (Table 1). The diagnosis was >3 times as likely among infants born to mothers with a history of eczema, compared with those born to mothers with no such history. Paternal history of eczema did not influence the likelihood of AD, whereas paternal history of hay fever was associated with less occurrence of AD (Table 2).

Cytokine Profiles
The proportions of samples with detectable cytokine concentrations were 22% for IL-2, 1% for IL-4, 87% for IL-6, 99% for IL-8, 46% for IL-10, 43% for granulocyte/macrophage colony-stimulating factor, 31% for IFN-, 55% for TNF-, 52% for IL-1β, 36% for IL-5, 91% for IL-7, 16% for IL-12, 30% for IL-13, 48% for IL-17, 70% for granulocyte colony-stimulating factor, 100% for MCP-1, and 100% for MIP-1β. No additional analyses of IL-4 were performed, because of the small number of samples with detectable concentrations. Associations between cord blood cytokines and AD outcomes were analyzed first as a categorical variable (detectable or undetectable) and then in terms of concentrations. There was no difference in the categorical variable for each cytokine between children with and without AD (data not shown). Table 3 compares cytokine concentration profiles in cord blood samples from infants with or without development of AD during their first year. MIP-1β levels were significantly lower in samples from infants who developed AD than in those from infants who did not. A trend toward decreased IL-7 and MCP-1 concentrations in infants with AD fell short of significance (Table 3). Unlike AD, infants who developed infantile eczema had significantly higher cord blood concentrations of IL-5, IL-17, and MCP-1 than did those who did not (Table 3).

Multivariate logistic regression analysis was used to assess independent effects of the various postnatal and prenatal risk factors on development of AD (Table 5). All factors that approached significance with Pearson ² tests, Student's t tests, or Mann-Whitney U tests were included in the model, that is, paternal hay fever, maternal eczema, MIP-1β levels, surface moisture content on the forehead and cheek, and moisture content of the stratum corneum of the forehead and cheek, all at the age of 1 month. Paternal hay fever (OR: 0.129; 95% CI: 0.020–0.845), MIP-1β levels (OR: 0.982; 95% CI: 0.967–0.998), and moisture content on the surface of the cheek at an age of 1 month (OR: 3.189; 95% CI: 1.279–7.952), but no other factors, were significant predictors of AD in the best-fitting model.

	DISCUSSION

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We determined the cumulative incidence of maternally reported, physician-diagnosed AD in the cohort of infants studied to be 27 cases (12.4%) among 213 children, in essential agreement with other epidemiologic studies in the United Kingdom¹² and the German Multicenter Atopy Study,¹³ which showed that 14% and 13.4% of subjects, respectively, developed AD in the first year of life. Our study demonstrated increased risk of AD for infants born to mothers with a history of eczema, which is consistent with previous reports that a positive maternal history predicted greater risk for childhood eczema than did a positive paternal history.¹⁴ Atopy may be inherited preferentially through the maternal line or mothers may carry relatively more of the predisposing genes. Interestingly, we found a negative relationship between AD and paternal history of hay fever caused by Japanese cedar pollen. Genetic susceptibility to hay fever apparently does not contribute to the development of AD in children; indeed, paternal hay fever might provide a child with some protection against developing AD. Kurzius-Spencer et al⁷ similarly found evidence of an apparent protective effect of paternal asthma, but mechanisms underlying these protective effects remain unknown.

Environmental influences during pregnancy and early life, particularly those related to hygiene and infections, seem to increase risks of asthma and allergic disease. In fact, certain infectious complications during pregnancy, such as respiratory tract infections, have shown associations with the development of asthma in childhood.^15,16 However, we could not detect associations between maternal viral or bacterial infections and the development of AD in children. This disagreement might involve differences in prenatal and postnatal actions of risk factors between various allergic diseases. For example, Calvani et al¹⁷ demonstrated that most such factors affected mainly the risk of nonatopic but not atopic asthma. Another possible explanation is that our study was prospective, whereas most others had a cross-sectional design.

In the present study, cord blood concentrations of IL-6, IL-8, IL-10, granulocyte/macrophage colony-stimulating factor, TNF-, IL-1β, IL-7, IL-17, granulocyte colony-stimulating factor, MCP-1, and MIP-1β were measurable in >40% of samples. However, other cytokines rarely were present in detectable amounts. The reason for the small number of samples with detectable concentrations of these cytokines might be related to suboptimal methods used for their quantification, because assays for some of the cytokines are known to be technically difficult. Alternatively, it is possible that various immune functions, including the capacity to secrete some cytokines, are attenuated at birth.^5,18 We could perform no additional analyses of IL-4 because the proportion of samples with detectable concentrations was only 1%.

In the present study, we found negative relationships between cord blood concentrations of MIP-1β and the risk of AD during the first year of life. We know of no previous reports suggesting that MIP-1β within the fetoplacental unit might influence susceptibility to subsequent disease development. The ability of chemokines to regulate Th1 and Th2 responses suggests that these mediators may take part in the pathogenesis of atopic diseases such as allergic asthma, for which Th2 response dominance has been observed. Influences of MIP-1, MIP-1β, and regulated on activation, normal T cell expressed and secreted in the establishment of Th1 responses have been reported.¹⁹ Grob et al²⁰ demonstrated intracellular expression of MIP-1β in CD4⁺ and CD8⁺ T cells from patients with allergic asthma to be significantly less than that in cells from subjects without asthma. This observation of diminished MIP-1β production by both CD4⁺ and CD8⁺ T cells suggests the relevance of this chemokine to disease development, with relative deficiency being likely to reflect dominance of Th2 responses over Th1 responses at the chemokine level. This view was supported by our present findings showing that low concentrations of cord blood MIP-1β were related to the risk of AD during the first year of life.

Infants with AD showed a trend toward lower concentrations of IL-7 and MCP-1, although the trend did not reach significance. Schonland et al²¹ demonstrated IL-7 to be a powerful stimulator of neonatal T cells, driving most CD4⁺ and CD8⁺ T cells into the cell cycle. Furthermore, the combinations of IL-4 and IL-12 with IL-7 were found to provide superior enhancement of antigen-specific T cell proliferation.²² Although MCP-1 was originally described for its chemotactic activity on monocytes, in vitro studies revealed an even higher activity on T cells.²³ Low concentrations of IL-7 and MCP-1 at birth may lead to impairment of T cell activation; therefore, infants may develop AD later during the first year of life. Another possible explanation for the lower cytokine levels might be secondary phenomena attributable to a different pattern of specific cell subtypes within the blood of these children. Additional studies are needed to confirm whether infants with AD have significantly lower concentrations of IL-7 and MCP-1 at birth.

In 1997, the European Group for Efficacy Measurements on Cosmetics and Other Topical Products gave recommendations regarding electrical measurement methods.²⁴ According to those recommendations, both single-frequency and multifrequency instruments may be used to assess skin hydration. High-frequency measurements in general reflect the deeper living layers of the skin, whereas low-frequency measurements are dominated by the stratum corneum. In the present study, we used a novel moisture meter (ASA-M1) that measures electrical admittance and susceptance at different excitatory frequencies.¹⁰ We found significant differences between functional skin variables in neonatal life and infancy at the age of 1 month, as well as differences between regions for both neonates and infants. This suggests that stratum corneum function was still adapting to extrauterine life during the period studied. A similar conclusion was drawn when skin surface capacitance and electrical conductance were examined in newborns.²⁵ Hoeger and Enzmann²⁶ found a significant increase in stratum corneum hydration, paralleled by a decrease in skin roughness, in serial measurements at 3 days, 4 weeks, and 12 weeks of age.

To our knowledge, no studies have monitored skin function parameters prospectively, to compare directly children with and without subsequent development of AD. In the present study, we found no differences in the moisture content of the surface or stratum corneum, measured a few days after delivery, between infants with and without development of atopy. In contrast, we found significant differences in the moisture content of the surface and stratum corneum on the face at the age of 1 month. Only 6 of 27 infants who developed AD during their first year had facial infantile eczema at 1 month. Although the other 21 infants had no eczema on the face, certain differences in skin function parameters were demonstrated at 1 month between infants with and without subsequent AD. These data suggest that differences in skin physiologic features between infants with and without AD emerge during the first month of life but not in the first few days. We do not know the mechanisms underlying changes in skin function parameters in infants with AD during the first month of life, but abnormalities during this period may be related to impairment of skin adaptation to extrauterine life.

Dry skin, leading to skin barrier disruption, has attracted attention as a nonallergic etiologic factor in AD.⁹ Several studies have demonstrated lower water-holding capacity in visually "uninvolved" skin of children with AD, compared with children without AD.⁸ Contrary to our expectation, infants with AD had more moisture content in the surface and stratum corneum at the age of 1 month than did infants without AD. The earliest lesions of infantile AD are erythematous weepy patches on the cheeks, with subsequent extension to the rest of the face and neck. With increasing age, there is a tendency toward drying and thickening of the skin in the involved areas. Therefore, our findings at the age of 1 month may be consistent with the earliest lesions in the clinical course of infantile AD. Furthermore, Yosipovitch et al²⁵ found a positive relationship between stratum corneum hydration, as evaluated with capacitance measurements, and transepidermal water loss (which reflects skin barrier function in newborns), which indicates that electrical properties of newborn skin may provide an indirect measurement of transepidermal water loss; this was also suggested by Saijo and Tagami²⁷ and Okah et al.²⁸ It will be necessary to monitor the skin physiologic features of these infants during the first year, to understand when the findings may eventually change into dry skin, leading to the defective skin barrier that is known in AD.

Infants with infantile eczema at the age of 1 month showed differences in immunologic and skin physiologic parameters, compared with findings for infants with later development of AD during the first year of life. In fact, infants with infantile eczema showed significantly higher concentrations of IL-5, IL-17, and MCP-1. These data suggest that the intrauterine environment is more likely to reflect the development of infantile eczema, rather than that of AD. Recent data indicate that the proinflammatory cytokine IL-17 stimulates the recruitment and activation of neutrophils and macrophages.²⁹ Furthermore, IL-17 regulates expression of adhesion molecules and chemokines in keratinocytes, which participate actively in skin inflammatory diseases.³⁰ MCP-1 has been shown to induce the migration of monocytes, which form a significant component of the inflammatory reaction taking place in the skin. Accordingly, higher concentrations of IL-17 and MCP-1 in cord blood of infants who later develop infantile eczema at the age of 1 month may contribute to the enhancement of inflammatory reactions in the skin of these infants. Infants who developed infantile eczema showed no difference from those who did not in stratum corneum moisture content for any region or time point, whereas a significant difference was seen for infants who developed AD during their first year. The reason for the difference in skin physiologic parameters for infants with eczema at the age of 1 month and infants with later development of AD during the first year of life remains unknown. However, measurements of skin physiologic parameters seem to be useful to distinguish infants with later development of AD from those with infantile eczema at the age of 1 month.

	CONCLUSIONS

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Our findings indicated that development of AD in infancy may be related to a decrease in MIP-1β production at birth, greater skin moisture in the surface of the cheek at 1 month of age, and paternal hay fever, in multivariate logistic regression analysis. The majority of risk factors had different effects on infant eczema and AD, which indicates different causes. The number of samples investigated in the present study might be small; larger prospective studies would serve to confirm our results and to explain the possible mechanism of how these factors act.

	ACKNOWLEDGMENTS

 
This work was supported in part by health sciences research grants for research on eye and ear sciences, immunology, allergy, and organ transplantation from the Ministry of Health, Labor, and Welfare of Japan.

We thank Tomoko Endo and Chihiro Ijima for their technical assistance.

	FOOTNOTES

 
Accepted Sep 22, 2006.

Address correspondence to Hirokazu Arakawa, MD, PhD, Department of Pediatrics and Developmental Medicine, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan. E-mail: harakawa{at}showa.gunma-u.ac.jp

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

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