Retention of Vernix Caseosa in Newborns for Primary Prevention of Atopic Dermatitis

Scientific Rationale:

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disorder that typically begins in early childhood and is characterized by pruritic eczematous lesions, epidermal barrier dysfunction, and immune dysregulation. Its prevalence is rising globally, affecting 10-35 % of children in industrialized countries. In Chile, epidemiological studies show that 18-22 % of school-aged children and up to one third of toddlers have physician-diagnosed AD, indicating a substantial and increasing disease burden. AD is often the first manifestation of the "atopic march," leading to food allergy, asthma, and allergic rhinitis.

Although several biologic and small-molecule therapies have recently transformed the management of moderate-to-severe AD, these treatments remain costly, inaccessible for most patients, and do not prevent disease onset. Therefore, identifying effective and feasible primary prevention strategies is a major unmet need.

Current understanding of AD pathogenesis highlights three interacting domains: (1) structural and biochemical defects of the epidermal barrier; (2) skewed type-2 immune responses; and (3) altered skin microbiota with increased colonization by Staphylococcus aureus. Defects in epidermal proteins such as filaggrin (FLG) increase transepidermal water loss (TEWL) and permeability to allergens and microbes, while immune activation and microbial imbalance perpetuate inflammation. Because these abnormalities emerge early in life-often before clinical symptoms-interventions targeting skin-barrier maturation and microbial balance during the neonatal period may reduce AD incidence.

Vernix Caseosa as a Natural Barrier Protector:

Vernix caseosa (VC) is a unique biofilm-like substance produced in utero by fetal sebaceous glands and composed of water (≈ 80 %), lipids (≈ 10 %), and proteins (≈ 10 %) intermingled with corneocytes. It covers the fetus during the third trimester, protecting the skin from maceration in the amniotic environment and promoting terminal differentiation of the stratum corneum. VC exhibits semipermeable and antimicrobial properties, functioning as a physiological barrier and innate immune interface. Its lipids include ceramides, cholesterol, and free fatty acids-key constituents of postnatal epidermal barrier repair-while its proteins include antimicrobial peptides such as LL-37, psoriasin, RNase 7, and lysozyme, as well as enzymes involved in lipid metabolism.

Despite these potential benefits, in many institutions worldwide VC is routinely removed within hours after birth as part of standard newborn cleaning procedures. Early removal eliminates a biologically active matrix that may support optimal skin barrier transition from intrauterine to extrauterine life. Small randomized and observational studies suggest that delaying vernix removal increases skin hydration, lowers skin pH, and may reduce bacterial colonization by S. aureus and E. coli, but evidence is limited by short follow-up and small sample sizes and no studies have evaluated its long-term impact on incidence of atopic dermatitis and other conditions.

The PROTEGO trial aims to test whether retaining vernix caseosa after birth, compared with its routine early removal, reduces the risk of developing AD during the first year of life and improves biophysical and microbiological indicators of skin health.

Study Design:

PROTEGO is a multicenter, randomized, controlled, parallel-group clinical trial with assessor blinding. The trial will enroll 1,383 pregnant women and their newborns from three high-volume maternity hospitals in Santiago, Chile. Eligible participants are healthy mothers ≥ 18 years of age with singleton pregnancies and expected delivery of a healthy neonate (≥ 34 weeks, birthweight ≥ 2000 g). After written informed consent, participants will be randomly assigned 1:1 via a centralized interactive response technology (IRT) system to either the vernix retention group or the vernix removal group. Randomization is stratified by clinical site, mode of delivery (vaginal/cesarean), and parental history of atopy.

Because masking of the delivery team and parents is not feasible, the study will use single-blind assessment, ensuring that investigators evaluating outcomes remain unaware of group assignment. Participants will be followed from birth to 12 months through scheduled visits (at 24-96 h; 7 days; and 1, 3, 6, 9, and 12 months).

Safety and Monitoring:

Retention or removal of VC are standard practices varying between institutions and are considered a minimal-risk intervention. Potential risks include mild skin irritation, transient erythema, or theoretical risk of hypothermia if bathing is delayed excessively. These will be mitigated by standard neonatal thermal-care protocols and skin monitoring. Adverse events (AEs) and serious adverse events (SAEs) will be actively monitored and reported according to institutional and national regulations.

Expected Impact:

If vernix retention proves effective, this trial could introduce a simple, low-cost, and universally applicable strategy for the primary prevention of atopic dermatitis. Because the intervention involves modifying routine newborn care rather than introducing new drugs or devices, it has high translational potential for maternity wards worldwide, especially in low- and middle-income settings.

Beyond its clinical endpoint, PROTEGO will generate valuable mechanistic insights into early-life skin-barrier biology, the neonatal microbiome, and gene-environment interactions (e.g., FLG variants). The integrated biophysical, microbiological, and transcriptomic datasets may illuminate new pathways linking perinatal skin care and immune development. PROTEGO is the first large-scale randomized controlled trial evaluating whether the simple act of preserving vernix caseosa after birth can prevent atopic dermatitis. By combining clinical follow-up with state-of-the-art barrier and microbiome analyses, this study seeks to redefine evidence-based newborn-skin care and contribute to global efforts to reduce the burden of allergic and inflammatory diseases from the very beginning of life.

• Incidence of Atopic Dermatitis (Hanifin & Rajka Criteria Only) [Срок оценки: 12 months.]
• Cumulative Incidence of Atopic Dermatitis (Modified UK Working Party Criteria Only) [Срок оценки: 0-12 months]
• Cumulative Incidence of Infant Eczema [Срок оценки: 0-12 months]
• Atopic dermatitis diagnosed by trained physician [Срок оценки: 12 months]
• Parent-reported atopic dermatitis [Срок оценки: 0-12 months]
• Cumulative incidence of atopic dermatitis by CEQ at 12 months [Срок оценки: 0-12 months]
• Use of topical anti-inflammatory medications [Срок оценки: 0-12 months]
• Time to onset of AD based on parent-reported age at first appearance among infants with AD [Срок оценки: From birth to 12 months of age]
• AD severity measured by the Patient-Oriented Eczema Measure (POEM) among infants with AD [Срок оценки: From birth to 12 months of age]
• Severity of Atopic Dermatitis (SCORAD) among infants with AD [Срок оценки: 12 months of age]
• Global AD severity based on parental assessment among infants with AD [Срок оценки: From birth to 12 months of age]
• Interaction of intervention with visible vernix caseosa (VC) at birth [Срок оценки: 0-12 months]