Emollients to Prevent Pediatric Eczema: A Pragmatic and Decentralized Randomized Clinical Trial

Abstract

Importance:

Atopic dermatitis (AD) imposes a global health burden for children and is a risk factor for developing food allergy and asthma. Few studies have evaluated emollient intervention for primary AD prevention in infants not selected for risk.

Objective:

To determine whether emollient intervention in infants not selected for risk reduces AD incidence by 24 months of age.

Design, Setting, and Participants:

We performed a randomized, decentralized pragmatic clinical trial involving 1247 infant-parent dyads recruited from 25 community-based pediatric and family medicine clinics that are members of four statewide practice-based research networks. Participants were recruited from 2018-2021 with follow-up completed through 2023.

Intervention:

Dyads were randomized to one of two groups: daily full-body emollient application Daily Moisturizer group starting by 9 weeks of age or a Control group that refrained from emollient use.

Main Outcomes and Measures:

The primary outcome was physician-diagnosed AD recorded in the patient’s medical record by 24 months of age. Participants completed quarterly electronic surveys to report adverse events and alert the team if an AD diagnosis had been made. Trained research coordinators abstracted participants’ medical records.

Results:

At 24 months, the cumulative incidence of AD was 36.1% (SE 2.1) in the Daily Moisturizer group and 43.0% (SE 2.1) in the Control group, with a relative risk (RR) of 0.84 (95% CI 0.73-0.97, p=.019) and the magnitude of effect was larger in the population not at high-risk of AD (RR 0.75, 95%CI 0.6-0.9, P=0.008). The protective effect was significantly modified by the presence of a dog in the home (RR 0.68, 95%CI 0.5-0.9, P=0.005). There were no between-group differences in cutaneous adverse events.

Conclusions and Relevance:

Daily emollient application beginning before 9 weeks of age in a representative U.S. population not selected for risk reduces the cumulative incidence of AD at 24 months of age. Implementing this approach to pediatric skin care may be a feasible way to reduce the burden of AD in U.S. communities.

Trial registration:

Clinicaltrials.gov Identifier: NCT03409367

Introduction

Pediatric atopic dermatitis (AD) imposes a substantial community healthcare burden in U.S. primary care clinics and represents a global health burden.(1) (2) Children developing AD early in life carry a risk of developing allergic comorbidities, sleep disturbance due to pruritus, behavioral challenges, bullying, and mental health disorders.(3) Recent studies reveal cutaneous inflammatory biomarkers precede AD development, suggesting the skin to be an important initiating site of the disease.(4) Loss-of-function FLG mutations, the strongest genetic risk factor for AD, can impair skin barrier function prior to the development of AD, indicating the skin may initiate AD through impaired barrier function.(5) Thus, protecting the skin barrier has been central to several AD prevention studies.

Over 10 randomized clinical trials enhancing the skin barrier to prevent AD have been performed with conflicting results.(6) Most trials have been conducted in high-risk populations and not in community primary care settings, a first point of care for most infants. Studies evaluating full-body emollient intervention for the primary prevention of AD in a population not selected for risk are lacking. The objective of this current study entitled the Community-based Assessment of Skin Care, Eczema, and Allergies - the CASCADE Trial - was to determine whether once-daily full-body emollient starting within the first 9 weeks of life can reduce the cumulative incidence of AD in a community-based population not selected for risk.

Methods

This study was approved by a central Institutional Review Board (IRB) at the University of Utah (IRB00106351) with IRBs at the University of Wisconsin, University of Colorado, Duke University, and Oregon Health & Science University agreeing to rely on the University of Utah. Study reporting adhered to the Consolidated Standards of Reporting Trials (CONSORT) 2022 statement.(7)

The CASCADE trial was a randomized, parallel-group, controlled, single-blind pragmatic 24-month clinical trial with a decentralized outcomes reporting structure. Decentralized trials minimize or eliminate the need for participants to travel to a centralized study center. Data are collected using remote or electronic methods and interventions are distributed by mail or email.(8) Both protocol and key participant-facing communications were reviewed and approved by a Community Advisory Committee composed of primary care providers and patient advocates. Key elements of the trial have been previously published.(9) Briefly, parent-infant dyads were recruited from 25 primary care clinics from 4 states in the U.S. and enrolled during scheduled well child clinic visits using an electronic tablet or personal electronic device. Inclusion criteria included: child aged 0-8 weeks, parents/guardians communicated in English or Spanish, had e-mail and internet connectivity. Exclusion criteria included: infants with a prior eczema diagnosis, were extremely premature (<25 weeks gestation) or very low birth weight (<1000g), had an immunodeficiency syndrome, or a sibling in the study. Eligible parents/guardians used Research Electronic Data Capture (REDCap) to provide electronic informed consent, complete the baseline questionnaire, and be randomized into the Daily Moisturizer (intervention) or the Control arm.

Randomization and Blinding

Participants were randomized in a 1:1 allocation ratio, stratified by primary care clinic and history of AD in a first-degree family member. Randomization sequences with blocks of four were created by the biostatistician (K.R.) using a computer-based random number generator to assign arms “1” and “2”. The Data Coordinating Center (DCC) programmed the REDCap randomization module and determined which number designated the treatment or Control arm.

Intervention

All parents received general skin care instructions suggesting bathing their child twice per week with gentle cleanser according to contemporary guidelines (10) that have now been updated.(11) Participants in the Daily Moisturizer arm selected an emollient from five bland emollient options that was mailed to the participant’s home every 6 months. Included emollients were selected for their ability to improve skin barrier function and lack of irritants and common allergens.(12–14) These choices were confirmed as common and appropriate recommendations by eight pediatric dermatologists or pediatric eczema experts at three universities and one private practice. Participants assigned to the Daily Moisturizer group were instructed to use the supplied emollient applied to the entire body once daily. The scalp and diaper area could be excluded from emollient use if preferred by the family. In the Control group, participants were instructed to refrain from routine frequent emollient use. Emollient could be used intermittently for dry skin in the Control group if deemed necessary by the family.

Primary Outcome

The primary outcome was the cumulative incidence of AD at 2 years of age as determined by a credentialed healthcare clinician and recorded in the healthcare record. Clinicians involved in the study were trained in AD diagnosis with comprehension checks.(15) Structured chart audits were completed by trained assessors who were blinded to study arm to collect the primary outcome.

Secondary Outcomes

Chart auditors collected information on AD diagnosis, skin infections, hay fever/allergic rhinitis, asthma, wheeze, food allergy testing, adverse events secondary to skin products and serious adverse events at 24 months (21-27 months). Quarterly and annual surveys gathered information on emollient use frequency in both groups, alternate AD definitions, reported provider-diagnosed food allergy, skin care-related adverse events and any serious adverse events.

Alternate AD definitions were gathered. The U.K. Working Party (UKWP) AD assessment was modified to remove the visible flexural eczema evaluation as originally designed.(16, 17) The Children’s Eczema Questionnaire (CEQ) was collected and has validation in children under four years of age; whereas, the UKWP criteria do not.(18) The third approach asked whether a clinician has diagnosed the child with AD - a question validated in other studies.(19) Participants who reported a diagnosis of AD by their clinician or met CEQ criteria were asked to complete the Patient-Oriented Eczema Measure (POEM), and the Infant Dermatology Quality of Life (IDQoL).(20, 21)

Statistical Analysis

Statistical analyses were performed by K.R. and supervised by J.L. The assumption was the Control group cumulative incidence of AD by age 2 would be 24% based on literature review and our own work(22, 23). We hypothesized that the intervention would provide a 30% reduction in risk, based on results from previous studies of emollients. Because an interim analysis was planned (see SAP for further details), the O’Brien-Fleming group sequential spending function was used to set the overall type 1 error at 0.05 and found that a total of 982 infants (491 per arm) were required to detect differences between the arms. Allowing for an approximate 20% loss to follow-up, we planned to recruit 1,250 dyads (625 per arm). The final analysis used a Type I error threshold of 0.05.

In the primary analysis, the risk of diagnosed AD by two years of age in the intervention was compared to the Control groups under an intention-to-treat (ITT) assumption and missing outcomes were imputed using multiple imputation. The relative risk (RR) was estimated using a generalized linear model with a binomial distribution and log link and reported p values from a two-sided Wald test at the 0.05 level of significance. Risk differences are presented using the margins and mimrgns commands in Stata software, version 18.

Missing values, including outcomes, were imputed using multiple imputation by chained equations (MICE). The number of imputation sets was determined by 100*(missingness fraction of the primary outcome).(24) Additional details are provided in the SAP including alternate AD diagnoses, secondary outcome analyses and sensitivity analyses.

We investigated differences in treatment effect in subgroups with risk or protective associations with AD. Subgroups included family history of atopy, dry climate, interaction with pets and farm animals at baseline, child’s age at randomization, more frequent bathing, and Caesarean birth.

Results

Population

From July 2018 to February 2021, 1,872 infant-parent dyads were screened and 1,247 were randomized. (Figure 1 and eTable 1 in the supplement). Baseline characteristics (Table 1) were balanced between study arms. The racial and ethnic composition of the study population closely reflected the ethnic and racial make-up of the U.S.(25) Thirty-five percent of participants were enrolled from practices in rural areas (as described by the practice).

Figure 1.

CONSORT Diagram

Table 1.

Baseline characteristics

	Daily Moisturizer (n=603)	Control (n=625)	Total (n=1228)	diff
Atopy in parent or sibling
Yes	296 (49.1)	303 (48.5)	599 (48.8)	0.012
No/Don’t know	307 (50.9)	322 (51.5)	629 (51.2)
State
Colorado	132 (21.9)	136 (21.8)	268 (21.8)	0.025
North Carolina	146 (24.2)	154 (24.6)	300 (24.4)
Oregon	222 (36.8)	224 (35.8)	446 (36.3)
Wisconsin	103 (17.1)	111 (17.8)	214 (17.4)
Sex
Girl	279 (46.3)	274 (43.9)	553 (45.1)
Boy	324 (53.7)	350 (56.1)	674 (54.9)	0.047
Age at randomization (days), mean (SD)	23.9 (16.0)	24.0 (16.6)	23.9 (16.3)	0.009
Moisturizer use before enrollment
Yes	391 (65.4)	382 (62.4)	773 (63.9)	0.062
No	207 (34.6)	230 (37.6)	437 (36.1)
If yes, days per week, mean (SD)	2.6 (2.1)	2.8 (2.1)	2.7 (2.1)	0.095
Domestic animals
Dogs	334 (55.4)	317 (50.8)	651 (53.1)	0.092
Cats	168 (27.9)	179 (28.7)	347 (28.3)	0.018
Farm animals	28 (4.6)	27 (4.3)	55 (4.5)	0.015
Ethnicity
Hispanic or Latino	144 (24.8)	141 (23.5)	285 (24.1)	0.030
Not Hispanic or Latino	437 (75.2)	459 (76.5)	896 (75.9)
Racea
American Indian or Alaska Native	24 (4.2)	7 (1.2)	31 (2.7)	0.185
Asian	39 (6.8)	38 (6.4)	77 (6.6)	0.013
Black	72 (12.5)	72 (12.2)	144 (12.3)	0.008
Native Hawaiian or Pacific Islander	5 (0.9)	5 (0.8)	10 (0.9)	0.002
White	497 (86.1)	523 (88.6)	1,020 (87.4)	0.076
Other	6 (1.0)	3 (0.5)	9 (0.8)	0.061
Education
Did not finish high school	26 (4.5)	23 (3.8)	49 (4.1)	0.150
High school degree or GED	98 (16.8)	127 (21.2)	225 (19.0)
Some college education	160 (27.4)	137 (22.9)	297 (25.1)
4-year college degree	120 (20.5)	136 (22.7)	256 (21.7)
Professional degree	180 (30.8)	175 (29.3)	355 (30.0)
Primary care practice settingb
Urban	209 (34.7)	223 (35.7)	432 (35.2)	0.028
Suburban	227 (37.6)	227 (36.3)	454 (37.0)
Rural	167 (27.7)	175 (28.0)	342 (27.9)

Percents calculated using non-missing responses in denominator. Responses were considered missing if respondents indicated that they preferred not to answer questions about the sex (n=1), ethnicity (n=47), or race (n=61) of their child or about their own education level (n=46).

^aRace percentages sum to >100 because respondents could indicate more than one category.

^bAs reported by practice representative at study start.

Intervention

At baseline, emollient option 4 was the most commonly selected emollient (eTable 2 in the supplement) in the Daily Moisturizer group (38.3%) but switching between emollients was common (eFigure 1 in the supplement). Over 50% of the Daily Moisturizer group reported 7 applications per week whereas over 50% of the Control group reported 0-1 applications per week (Figure 2 and eTable 3 in the supplement).

Figure 2.

Parent-reported moisturizer use over time by study arm (Moisturizer n=603, Control n=625 babies)

The annual survey completion rate was 90.1% for the 12-month survey and 88.3% for the 24-month survey. Fewer than 20% of participants in both study arms had missing primary outcomes (Figure 2).

Primary Endpoint and Sensitivity Analyses

At two years, the cumulative incidence of AD per adjudicated primary care clinician-reported chart diagnosis (primary outcome) in the Daily Moisturizer group was 36.1% (SE 2.1) and 43.0% (2.1) in the Control group (Figure 4). The cumulative incidence of AD in the Daily Moisturizer group was significantly lower than the Control group, RR 0.84, 95% CI 0.73-0.97, P=.019. The results were consistent with a protective effect of emollients for all case definitions except for the UKWP criteria, which has not been validated for children (Figure 4). The study was not powered to detect differences in AD incidence by emollient type and discerning the relative potency of each emollient for AD protection was not possible (eFigure 2 in the supplement) given emollient switching.

Figure 4.

Cumulative incidence, risk difference, and interaction (effect modification) for the risk of atopic dermatitis (AD) by age 24 months for subgroups (Moisturizer arm n=603, Control arm n=625 babies). Intent-to-treat analysis with multiple imputation for missing outcomes.

Effect Modification

Having a first-degree blood relative with atopic disease (i.e. high-risk) was associated with a weaker intervention effect than for children at lower risk, although the interaction was not statistically significant (Figure 4). Among children at low risk, the cumulative incidence in the Control arm was 43.4% compared to 33.2% in the intervention, a statistically significant −10.1% risk difference (RD; 95% CI −18.1 to −2.2). Among children at high risk, the Control arm had a similar cumulative incidence (42.5%) but the RD associated with the intervention was only −3.4% (−11.9 to 5.1). The protective effect of emollient was significantly modified by dog ownership with a stronger protective effect of the intervention observed in this subset of families (RD= −14.2 [−23.2 to −4.6]) than in those without any pets (RD=0.3 [−9.6 to 10.3]).

Secondary Outcomes (eTable 5 in the supplement)

Skin infections occurred at slightly lower rates in the Daily Moisturizer group than the Control group (19.8% vs. 21.1%, RR 0.94, 95%CI 0.74-1.20) with no statistical difference between groups. Parental report of food allergy, defined as a reaction to a food within 90 minutes plus a typical Type I reaction such as vomiting or hives, was lower in the Daily Moisturizer group than in the Control group with no significant differences between groups (10.7% vs. 14.2%, RR 0.76, 95%CI 0.55-1.04). In those with AD, the median scores reflected mild disease for both POEM and IDQoL with a large range of disease severity (eFigure 3 and eTable 3 in the supplement). There were no clinically meaningful differences between groups in disease severity by either instrument.

Safety (eTable 6 in the supplement)

There were no differences in cutaneous skin product-related AE rate proportions between the two groups. “Rash” was the most frequent parent-reported AE and most AEs were mild to moderate in severity. While “rashes” were reported to be related to skincare product use, the exact etiology could not be precisely defined due to the limitations of participant-described AEs. There were no treatment-related SAEs.

Discussion

In this community-based study, a protective effect of daily full-body bland emollient application was observed at 2 years of age in an unselected population. The use of emollients reduced the risk of AD at 2 years of age by 16% which equates to a number-needed-to-treat of 15. These results were consistent across multiple definitions of AD including AD requiring prescription therapy. The magnitude of the effect of the intervention was stronger in babies without an atopic history in the family (24% reduction) and those reporting a dog in the household. The intervention appeared safe and feasible. Given the current and frequent use of moisturizers by the U.S. population,(26, 27) this intervention may represent a practical and safe approach to reducing the burden of AD in U.S. communities.

The results of this study add to a growing body of evidence regarding the potential role of emollient therapy for the prevention of AD. A Cochrane individual participant level meta-analysis did not find skin care interventions, taken together, to be protective against AD development, which included interventions that were not strictly emollient interventions.(28) Two additional systematic reviews reported a protective effect of emollients in high-risk populations with RRs estimated to be 0.74-0.75.(29, 30) Methodological concerns regarding one of these reviews have been published.(31) Only two individual studies evaluating populations not selected for risk have been performed. However, these studies did not test full-body emollients; one used bath oils and one used facial application of emollient only.(32, 33) Thus, the CASCADE trial is unique in that it evaluated full-body direct emollient application for the prevention of AD in a population not selected for risk.

The finding that an emollient intervention reduces the risk of AD to a greater degree in participants without a family history of atopic disease is a novel finding. One explanation for this observation may be that children with a strong atopic family history, which includes AD, asthma and hay fever, may have disease primarily driven by immune dysregulation, including genetic causes. Whereas those without an atopic family history may have AD initiated by skin barrier insults such as irritation from water, soap, dry indoor or outdoor climate, and additional unknown genetic factors, and thus are more amenable to skin barrier repair. Behaviors within families with atopic conditions may favor practices that reduce skin and allergy issues, such as more care in bathing practices and avoidance of irritants and allergens - behaviors not captured systematically in our study but that may blunt the effect of moisturizer use in this subgroup. A study of prenatal antibiotic exposures found more of an effect on risk of AD in offspring in low-risk families than higher risk for unclear reasons but suggests family history may modify effects of various exposures.(34) Future studies should ideally measure markers of immune dysregulation and known genetic risk alleles if feasible.

Another novel finding is the significant modification of the effect of emollients by household dog ownership status. Data regarding AD risk and pet ownership are conflicting but appear to provide a protective effect.(35) A recent birth cohort study from Japan (n=1440) found pet ownership reduced AD incidence only in babies without a FLG mutation. This suggests a child’s skin barrier status can alter the effects of household pet exposure.(36) This is consistent with our results that found dog ownership to enhance the protective effect of emollients, although the exact mechanisms underlying this observation requires further study.

Our findings suggest the routine use of emollients for prevention may be a feasible approach for families. Interestingly, 64% of participants reported using emollients prior to study enrollment. These findings are consistent with a previous survey from Oregon.(26) This suggests that routine emollient use is part of infant skincare routines for many households in the U.S. The composition of the emollient likely makes a difference in efficacy as differences have been observed in skin barrier assessments between ceramide and non-ceramide containing moisturizers.(37) Two of the five emollients in the study contained ceramides. Some emollients may even harm the skin barrier and theoretically promote AD.(38, 39)

The overall prevalence of AD was higher than expected at ~43% by two years of age. Rates close to this magnitude have been reported in a recent cohort in Scandinavia (n=1834) reported to be 34.2% at one year. (40) As in our study, this cohort found the UKWP criteria prevalence was lower due to a lack of fulfilling the itch criteria. The sensitivity and specificity of each definition in the CASCADE cohort are undergoing analysis to better understand discrepancies and will be the subject of a future manuscript. It is important to note that the protective effect was observed with similar magnitude across all disease definitions. The use of multiple definitions of AD may be useful in future studies.

The study identified no safety signals of concern with the emollient interventions. Fewer cases of contact dermatitis and “rash” were observed in the Daily Moisturizer arm suggesting emollient use may protect against conditions such as irritant contact dermatitis and diaper dermatitis. A previous large randomized controlled study found possible increases in both skin infection and food allergy with emollient use.(41) These trends were notably not observed in our study and the rates of both events were numerically lower in the Daily Moisturizer group.

The ultimate goal of this line of research is to develop skincare guidelines for families with young children that best protect against AD development. Reducing the burden of AD may also mitigate the risk of developing allergic comorbidities that are shown to be more prevalent in children with early-onset AD.(42) There are some data to suggest that systemic allergic responses may initiate from skin inflammation. Certain inflammatory serum biomarkers elevated in atopic diseases decrease following skin-directed therapies.(43) Promoting daily emollient use thus may have benefits not only on AD development but allergic diseases as a whole. Longer-term follow-up is needed to determine whether the reduction of AD translates to measurable reductions in the incidence of allergic comorbidity.

This study has several strengths. This is the first randomized trial utilizing primary care practice-based research networks studying an intervention for a dermatologic condition. The decentralized structure eased the study burden on participants, allowed enrollment of a diverse study population and led to low attrition rates.

Limitations of the study include a lack of understanding which emollient may be best to achieve effective prevention of AD, no genetic testing, and no formal food allergy testing. In addition, daily full-body moisturizer may be cost-prohibitive for some families, difficult to apply, cause contact dermatitis, or have unknown adverse effects from absorption of ingredients such as parabens with long-term use.(44) Emollients were provided free of charge for this study thus may not be generalizable to the current U.S. population.

In conclusion, full-body emollient application starting in the first 2 months of life reduced the risk of AD development, especially in those without a history of atopic diseases in the family and who have a dog in the household. Further work will be needed on the cost-effectiveness of this approach and implementation strategies. The impact of this approach on allergic comorbidities is also a high priority for future work.

Figure 3.

Cumulative incidence, risk difference, and relative risk of atopic dermatitis by age 24 months by the primary definition of documentation in chart and alternative methods to ascertain AD (Moisturizer arm n=603, Standard of Care arm n=625 babies). Intent-to-treat analysis with multiple imputation for missing outcomes.

KEY POINTS.

Question

Does daily emollient application from 9 weeks to 24 months of age help to prevent atopic dermatitis (AD) in a population unselected for risk?

Findings

In this randomized, pragmatic, decentralized trial we found that those who were assigned to the daily moisturizer group had a lower cumulative incidence of AD (36.1%, SE 2.1) compared to the standard of care group (43.0%, SE 2.1).

Meanings

Applying emollient daily in infants may be a feasible way to reduce the incidence of AD.

The CASCADE Trial Consortium includes the named authors and the following people, who served on the protocol steering committee, the community advisory committee, consultants, and PBRN leadership and staff. Additional Contributions: Janna B. Howard, Cat Halliwell, Jean Hiebert Larson, Nancy Elder, Shelbey Deegan, Meredith Warman, Sarah Bumatay, Mohammad Fazeel Hashmi, Sankirtana Danner, Karen Hansis, Joanne Chalmers, Jon Hanifin, Katharine Zuckerman, Mollie Gundersen, Julie Block, Susan Tofte, Sandra Dunbraski, Kathy Siebe, Kristen Dillon, Caitlin Dickinson.