Prevention of Atopic Dermatitis in High‐Risk Infants: A Review of the Role of Lipid‐Based Barrier Repair Therapy

ABSTRACT

Background/Objective

Growing evidence highlights the role of physiological lipids, namely ceramides, cholesterol, and free fatty acids, in maintaining skin barrier function and preventing atopic dermatitis (AD). Current evidence on the efficacy, safety, and clinical relevance of stratum corneum (SC) lipid‐based therapies to prevent AD and increase skin barrier integrity in high‐risk infants was reviewed and synthesized.

Methods

Searches with key words lipid‐based therapy, atopic dermatitis, infant, and prevention were conducted to identify papers using PubMed, Embase, Cochrane Library, and Scopus databases from January 2000 to June 2024.

Results

SC lipid‐based therapies were reported to replenish deficient SC lipids, thereby improving skin barrier function, a critical aspect of AD management. These therapies reduced SCORAD scores, enhanced hydration, and improved epidermal cohesion, with some studies reporting comparable efficacy to topical corticosteroids when used as adjunct treatments. However, evidence supporting their effectiveness in preventing AD onset in infants remains limited, with only trends toward reduced AD incidence and food sensitization reported, without statistical significance. Importantly, SC lipid therapies are well tolerated, with no significant adverse effects noted, supporting their safety in infants and children.

Conclusion

This review ascertained knowledge gaps that can direct research and resolve controversies regarding emollients. Mechanistic studies in high‐risk and non‐atopic infants, starting at birth, are warranted using within‐subject comparisons and frequent evaluations, including SC sampling for proteomics and lipidomics outcomes for mechanistic insight. Studies should begin with relatively simple formulations, for example, containing only ceramides, cholesterol, and fatty acids matched to varying infant SC lipid profiles at birth and over time.

1. Introduction

Neonatal and infant skin differ significantly from older children and adults in structure and function [1, 2]. It is thinner, more permeable, and has reduced glandular secretions, making it more vulnerable to environmental insults [1, 2]. Compared to adults, newborn skin has higher water content, initially lower natural moisturizing factor levels, higher pH, and lower transepidermal water loss (TEWL) [2]. Infant and young children's body surface area is higher, thereby increasing the risk for water loss. Postnatally, the neonatal skin undergoes gradual adaptation to the dry extra‐uterine environment, with full maturation taking up to a year [1].

Atopic dermatitis (AD), a chronic inflammatory skin condition, affects 13%–30% of children and 5% of adults worldwide [3, 4]. It is intensely pruritic, with xerosis, erythematous patches/plaques, and excoriations, significantly impacting quality of life, especially in infancy [3]. Infant AD often appears within the first three months, but may occur at any time [5]. Parental history of AD, asthma, allergic rhinitis, and skin barrier defects, for example, filaggrin (FLG) gene mutations, are risk factors [6]. AD pathophysiology involves a complex interplay of genetic predisposition, skin barrier lipid deficiency, immune dysregulation, environmental factors, and microbial imbalance [5, 6, 7, 8]. FLG maintains skin barrier structure by keratin aggregation and skin hydration via proteolysis to natural moisturizing factor (NMF) [9]. Loss‐of‐function FLG mutations lead to increased TEWL, reduced hydration, and heightened irritant vulnerability [7]. Recently, the intragenic copy number FLG gene has been independently associated with AD risk in the Irish population [10]. Other genes, for example, epidermal differentiation complex (EDC), FLG2, HRNR, and TCHH1, likely impact skin barrier quality [10]. Barrier deficiencies contribute to the chronic xerosis and sensitivity in AD [6, 7].

Immune dysregulation is another hallmark of AD pathophysiology [5, 7, 11]. A T‐helper 2 (Th2)‐dominant immune response drives inflammation [5, 7, 11], with key cytokines, that is, interleukin IL‐4, IL‐13, and IL‐31 contributing to barrier disruption and pruritus [3, 7]. The cytokines impair the synthesis of filaggrin and lipids, exacerbating barrier dysfunction and immune activation [5]. Chronic inflammation can shift the immune response toward Th22 and Th1 pathways that contribute to skin thickening and lichenification in chronic lesions [3, 7]. Immune dysregulation and barrier impairment increase disease progression [5, 12].

External factors, including irritants and low humidity, can damage the skin barrier and allow allergens to penetrate the compromised epidermis to increase TEWL and immune responses [3, 7]. Skin microbiome dysbiosis and overgrowth of Staphylococcus aureus drive inflammation, inhibit antimicrobial peptide synthesis, and increase infection risk [7, 12].

The stratum corneum (SC) lipid matrix consists of ceramides, cholesterol, and free fatty acids in a near‐equimolar ratio that forms lamellar bilayers between terminally differentiated keratinocytes to confer barrier integrity. It regulates hydration and prevents entry of harmful substances [1, 3, 5, 9]. Ceramides organize the lamellar bilayers [12, 13, 14]. The adult AD barrier has reduced total ceramides and specific ceramide subclasses versus non‐atopic adults [15] due to molecular effects of type 2 cytokine overexpression [5, 9, 10, 16]. This leads to impaired water retention, increased TEWL, and heightened susceptibility to microbial colonization and allergens [1, 5].

Managing pediatric AD is multifaceted [17]. While topical corticosteroids, calcineurin inhibitors, and biologics like dupilumab are key therapies, prevention remains critical [7, 8, 13]. Regular emollient application is a primary prevention strategy reducing reliance on topical steroids [18, 19]. However, evidence on the effectiveness of early emollient use to prevent AD in high‐risk infants is conflicting. While some studies support their preventive role [6, 20], others suggest they may be ineffective and increase risks of allergic sensitization and skin infection [1, 5].

Traditional emollients may contain humectants (e.g., glycerin, hyaluronic acid), occlusive (e.g., petrolatum, lanolin), vegetable oils, ceramides, emulsifiers, and excipients to attract and retain water in the stratum corneum [1, 5]. Skin barrier repair therapies have been formulated with the SC physiological lipids, namely, ceramides, cholesterol, and free fatty acids. They aim to restore the skin's normal lipid composition and structure [9, 21], reduce water loss, and increase hydration. They may restore the SC lipid balance to reduce inflammation and water loss and to increase hydration and skin barrier integrity, thereby preventing AD in high‐risk infants [5, 9]. This review synthesizes current evidence on the efficacy of SC lipid‐based barrier therapy as an early intervention to prevent/reduce AD and increase skin integrity in infants.

2. Methods

A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and Scopus for peer‐reviewed papers between January 2000 and June 2024. Keywords included “atopic dermatitis,” “lipid therapy,”, “infant,”, and “prevention,” combined with Boolean operators (AND, OR) and MeSH terms (“atopic dermatitis prevention,” “lipid‐based therapy,” and “infant skin barrier”) to maximize search sensitivity. Studies were retained if they focused on SC lipid treatments, that is, with ceramides, cholesterol and fatty acids, atopic dermatitis, neonates or infants, prevention, and were in English. Excluded were case reports, and articles without primary data (e.g., editorials, opinions). For studies with brand names, product compositions from company sources were listed. Of 100 citations, 30 were critically reviewed and data was extracted from 12 papers, analyzed and included.

3. Results

The results were in two categories: (1) lipid‐based therapies and mechanisms of skin effects and (2) efficacy of SC lipid‐based treatments for prevention and treatment in infants considered to be at high risk for developing AD.

3.1. SC Lipid‐Based Therapies

Ceramides, in combination with cholesterol and free fatty acids at an appropriate ratio, are the physiological basis of “lipid‐based” barrier repair therapy. The use of ceramide alone delayed skin barrier repair [22]. All 3 constituents, that is, ceramides, cholesterol, and free fatty acids, in an equimolar ratio are required to restore barrier function after the disruption of normal skin [22]. SC lipid therapies function differently than traditional moisturizers [22]. They do not form an occlusive layer on the SC surface and are quickly absorbed into the underlying nucleated cell layers [5]. Subsequently, these SC lipids are incorporated into lamellar bodies of the stratum spinosum and granulosum cells, thereby joining the de novo synthesized lipids prior to secretion into extracellular space [23]. To maximize efficacy, SC lipids should be present at a minimum of 5% of SC weight (~0.06 g/cm³) to mimic normal lipid density [5, 18]. Given AD's ceramide deficiency due to Th2 cytokine activity, the most effective ratio of the 3 lipids is a ceramide‐dominant mixture at approximately a 3:1:1 M ratio [5, 10].

3.2. Evidence Supporting Lipid‐Based Barrier Repair Therapy for AD Prevention and Treatment

The search identified 12 studies with relevant data (Table 1). Five trials totalling 837 infants examined the effect of SC lipid therapies on the incidence of AD. One infant study with a non‐SC lipid treatment (n = 118) was included for comparison. Four described pediatric subjects (n = 272) and 2 discussed adult responses (n = 88). Table 1 details the treatments/comparisons, study design, number of subjects, age, AD criteria, application frequency, duration, and outcomes. The majority had twice daily treatment (range 1–3), had 4 weeks treatment (range 2–32 weeks), began 4–21 days after birth, and had first‐degree family AD. The outcomes were typically AD incidence but included product adherence, food/inhalation sensitization, LoF FLG mutation response, SCORAD or EASI scores, and measures of TEWL, hydration, pH, dryness, infection, SC cohesion, and NMF. There were 8 different SC‐lipid treatments. Table 2 shows the SC lipid treatments, controls, and their compositions.

TABLE 1.

Study descriptions.

Study & design	No.	Treatment (Table 2)	No.	Age & criteria	Frequency & duration	Outcomes/Results
Infant Studies
Lowe [24] Parallel group	1	Ceramide, cholesterol, fatty acid (EpiCeram)	39	Full‐terms AD Family	2X daily 26 weeks	−Application start: Day 12 (4–28) −Adherence: of 33, 93% with 3X weekly; 76% 5 days/wk −AD incidence 3% wk. 6%, 10% 6 months, 5% 12 months −No differences: TEWL, pH, hydration, oiliness (sebum) −No adverse reactions
	2	No emollient	38	Full‐terms AD Family		−Adherence: of 28, 4.8% routine emollient use. −Adherence: 39% used emollient 3X/week in first 6 months −AD incidence 0% week 6, 17% 6 months, 16% 12 months
McClanahan [25] Parallel group	1	Ceramide, amino acids (Cetaphil Restoraderm)	54	Full‐terms AD (1st degree)	1X daily, start by day 21 Not scalp, diaper	−Adherence = 87% 2 months, 72.4% 6 months and 66.7% 12 months − ad 13.2% at 12 months, (p = 0.2), no difference − ad 19.4% at 24 months, (p = 0.3), no difference −Substudy (n = 32): TEWL, capacitance, no difference—pH increased to 5.46 test versus 4.98 control (p = 0.044) 8 weaks −SC cohesion, NMF, microbiome, no difference −Bacterial infections: 7.4% versus 6.5%, no difference −Hypersensitivity (ICD): 14.8% versus 8.7%, no difference
	2	Glycerin, triglycerides (J&J Head to Toe)	46	Full‐terms AD (1st degree)	As needed	−Adherence = 45.2% 2 months 45.8%, 6 months, 45.5% 12 months − ad 25.0% at 12 months − ad 27.8% at 24 months
Horimukai [26] Parallel group reduced AD but not sensitization	1	Oil in water emulsion (2e [Douhet])	59	Full‐terms Parent AD	1X day, day 4 to 32 weaks	−Treatment usage: 7.9 g/day − ad 32.2%, lower vs. control, p = 0.012 −Allergic sensitization, no difference −Skin hydration, higher versus control, p < 0.05 −−6.1% positive S. aureus cheek at birth; 22.4% wk. 12 − S. aureus, wk. 12, no difference
		Petrolatum per IRB	59	Full‐terms parent AD	Not stated	−Control (petrolatum) usage: 0.1 g/day − ad 47.4%, significant versus 2e emulsion −−6.1% positive S. aureus cheek birth; 22.4% wk. 12
Dissananyake [27] Parallel group	1	Ceramide, cholesterol, fatty acid (Locobase Repair)	138	Full‐terms No AD history needed	2‐3X day, especially cheeks, perioral Birth‐6 months	− ad 21% at 6 months; no difference −Serum TARC 1214 ± 975, no difference −EASI for AD at 9 months =3.6 (1.8–5.6), no difference −TARC for AD at 9 months = 1469 −Food allergies 12 months = 11%, no difference −Food allergy sensitization 9 months = 60.5% −Inhalation allergy sensitization 9 months = 9.2%
	2	No skin care	137	Full term, No AD history needed		− ad 18.8% at 6 months; no difference −Serum TARC 1047 ± 622 −EASI for AD at 9 months = 2.4 (0.2–11.3), no difference −TARC for AD at 9 months = 846 −Food allergies 12 months = 13% −Food allergy sensitization at 9 months = 46.1% −Inhalation allergy sensitization 9 months = 9.6%
Ng [28] Parallel group	1	Ceramide, fatty acid (Cetaphil Restoraderm Skin)	66	Full‐terms Both parent AD	Frequency not stated Start within 2 weeks	−Mod‐severe AD 4%, no difference −Overall ad 37%, no difference −Rate of new diagnoses higher at 2 month versus other, no dif −TEWL, hydration, pH, no differences & high variability −−8 of 151 were positive for LoF FLG mutation total −−5 developed AD −Drop‐out rate, 36% before month 2 −−38 subjects had skin prick test; 55.3% at least 1 positive, significantly higher
	2	No emollient	62	Full‐terms Both parent AD		−Mod‐severe ad 6%, −Overall ad 35% −Rate of new diagnoses higher at 2 months versus other times −Of the LoF FLG mutations, 3 developed AD −−35 had skin prick test; 22.9% at least 1 positive
Ni Chaoimh [6] Parallel group	1	Ceramide, fatty acid (Aveeno Dermexa)	161 enr 119 analysis	Full‐terms One parent AD	2X day 4 to 8 weeks; follow to 12 months	−Emollient 1X: 89% at 2 weaks, 89% 4 weaks, 91.7% 8 weaks −Emollient 2X: 63.3% 2 weaks, 69.2% 4 weaks, 73.1% 8 weaks − ad 32.8% 12 months, lower versus control, p < 0.05 −By per protocol analysis cum ad 35.2% 12 months, not reach significance (p = 0.078) −−18.3% AD at 6 month, lower versus control, p < 0.05 −By per protocol, 24.1% ad 6 month, lower versus control, p < 0.05 −−17.9% had LoF FLG mutation, no difference −Positive skin prick for at least one food = 5, no difference −TEWL no difference, any time −NMF near‐IR Raman spectroscopy no difference, any time
	2	Routine skin care advice	160 enr 138 analysis	Full‐terms One parent AD	No instruction for emollient	−Emollient ≥ 4 days/weak: 19%, 17.5%, 13.5% at 2, 4, 8 weaks −Emollient < 4 days/weak, 68% all times −−46.4% AD at 12 months, higher versus treatment, p < 0.05 −By per protocol analysis, 49.4% AD at 12 months, not reach significance (p = 0.078) −−35.0% AD at 6 months, higher versus treatment, p < 0.05 −By per protocol, 39.8% ad 6 months, higher versus treatment, p < 0.05 −−16.9% had LoF FLG mutation, no difference −Positive skin prick for at least one food = 4, no diff −TEWL no difference, any time point −NMF near‐IR Raman spectroscopy no difference, any time
Pediatric Studies
Sugarman [29] Parallel group	1	Ceramide, cholesterol, fatty acid to lesions (EpiCeram) Glycerin, and so forth to nonlesions (Cetaphil)	59	8 years (0.5–18) Mod‐severe AD	2X day, 4 weeks	−SCORAD decreased from 37.2 to 23.6 and 18.5 at weaks 2, 4 −Pruritus decreased from 6.1 to 3.9 and 2.8 −Sleep habits decreased from 4.1 to 2.2 and 1.4 −By ANOVA, treatments differed day 14 (p < 0.05), no difference day 28.
	2	Fluticasone propionate 0.05% to lesions Glycerin, etc. to nonlesions (Cetaphil)	62	7 years (0.6–16) Mod‐severe AD	2X day, 4 weeks	−SCORAD decreased from 34 to 15 and 11 at weaks 2, 4 −Pruritus decreased from 5.7 to 2.8 and 1.9 weaks 2, 4 −Sleep habits decreased from 4.1 to 1.3 and 0.7 weaks 2, 4
Somjorn [30] Paired, split body	1	Ceramide, linoleic acid, dexpanthenol (Provamed Derma)	37	2–18 years AD	Frequency not stated, 4 weeks	−SCORAD reduction greater for ceramide system, p < 0.05 −Time to 50% reduction, no difference −Skin hydration increase, no difference −Side effects, irritation, no difference
	2	5% urea	37	2–18 years AD	Frequency not specified, 4 weeks	−SCORAD score reduction, lower for urea, p < 0.05 −Time to 50% reduction, no difference −Skin hydration increase, no difference −Side effects, irritation, no difference
Gupta [31] Parallel group	1	Ceramide‐based (AquaOat)	27	9.0 ± 4.6 years AD	2X day, 6 months	−SCORAD decrease 22.1 at 3 month, no difference −TEWL forearm reduced 1.3 (−12.8–100.8), no difference −TEWL back reduced 2.3 (−9.8 to 17.9), no difference −Corticosteroid use 63 g at 3 month, no difference −Moisturizer use 1060 g (median), no difference −Complete remission 64%, no difference
	2	Paraffin‐based (Olesoft Max)	26	7.3 ± 4.3 ad	2X day, 6 months	−SCORAD decrease 21.4 at 3 months −TEWL forearm reduced by 2.5 (−3.1–23.9) −TEWL back reduced by 1.3 (−2,9–30.2) −Corticosteroid use 55 g at 3 months −Moisturizer use 1100 g (median) −Complete remission 76%
Chamlin [32] Single group	1	Topical steroid and/or tacrolimus Plus ceramide, fatty acid (TriCeram)	24	6.4 years AD	2X day, 12 weaks; Then 1X weaks 12–20	−SCORAD decrease from 53 to 30 weaks 6 then plateau. −TEWL decrease from ~43 to 22 weaks 6 then to 15 weaks 12; increase to 22 (weaks 20) after reduction to 1X application −Hydration increase from 21 to 28 weaks 6, then 32 weaks 12; increase to 36 weaks 20 after reduction to 1X application −Barrier integrity increase from 12 tapes to strip to 22 at weaks 6, 24 weaks 12 then 17 weaks 20 after reduction to 1X application
	2	Control	NA	NA	NA	−No control used
Adult Studies
Kircik [34] Paired, split body	1	Ceramide, cholesterol, fatty acid (EpiCeram)	10	31 years AD	Frequency not stated 4 weeks	−TEWL decrease by 15.9%, no difference −Hydration increase by 55%, no difference
	2	Paraffin based (Eucerin)	10	17 years (12–68) AD	Frequency not stated 4 weeks	−TEWL decrease by 14.5% −Hydration increase by 35%
Danby [33] Paired, split body forearm and lateral leg	1	Ceramides, triglycerides, cholesterol (CeraVe)	34	43 ± 18 years Dry skin	2X day 4 weeks	−Outcome: skin response to SLS under occlusion −Visual redness 0.5 lower, p < 0.05 −Instrumental redness 25.1 lower, p < 0.05 −TEWL 15.3 g/m2/h lower, p < 0.05 −Outcome: Skin barrier integrity −Protein 65.9 μg/cm2 lower, SC more cohesive, p < 0.05 −Slower TEWL increase with tape stripping, more cohesive −Skin hydration increase 10.1 and 8.61 at 2, 4 weaks, p < 0.05 −Visual dryness lower, 4 weaks, p < 0.05 −Increased lipid ester groups on surface (triglyceride) −Lipid ester groups not found in inner SC layers −Adverse reaction: 1 for Test, 7 for paraffin
	2	Paraffin‐based (Zerobase)	34	43 ± 18 years. Dry skin	2X day, 4 weeks

Abbreviations: AD, atopic dermatitis; EASI, eczema area and severity index; enr, enrolled; FLG, flaggrin; Freq., frequency; J&J, Johnson & Johnson; LoF, loss of function; mo, month; Mod., moderate; NA, not available, not applicable; near‐IR, near infrared; NMF, natural moisturizing factor; SCORAD, SCORing Atopic Dermatitis; SC, stratum corneum; TARC, thymus and activation‐regulated chemokine; TEWL, transepidermal water loss; Trt. No., treatment number; wks, weeks; X, times.

TABLE 2.

Topical treatments and ingredients for reviewed publications ingredients corresponding to the SC lipids in the SC lipid‐based therapies are in bold.

References	Treatments	Ingredients
Lowe [24] 2018	EpiCeram	Purified water, Multisal Neolipids*, glyceryl stearate, squalane, glycerin, PEG‐100 stearate, hydroxypropyl bispalmitamide MEA (ceramide), petrolatum, dimethicone, phenoxyethanol, cholesterol, conjugated linoleic acid, citric acid, palmitic acid, xanthan gum, potassium hydroxide, disodium EDTA, sorbic acid, capric acid; controlled‐release skin barrier emulsion. *Proprietary microencapsulation system for gradual delivery of key ingredients including ceramide, conjugated linoleic acid, cholesterol and palmitic acid (with Candelilla wax, corn syrup solids and modified food starch).
McClanahan [25] 2019	Cetaphil Restoraderm	Collodial oatmeal 1.0% water, glycerin, caprylic/capric triglyceride, sunflower seed oil, pentylene glycol, shea butter, cyclopentasiloxane, cetearyl alcohol, sorbitol, behenyl alcohol, glyceryl stearate, cetyl alcohol, tocopheryl acetate, arginine, niacinamide, glyceryl stearate citrate, sodium polyacrylate, disodium ethylene dicocamide peg‐15 disulfate, caprylyl glycol, ceteareth‐20, sodium pca, panthenol, citric acid, allantoin, dimethiconol, ophiopogon japonicus root extract, disodium edta, maltodextrin, sodium hyaluronate, ceramide np, pantolactone
	Johnson & Johnson Head to toe lotion	Water, glycerin, cocoglycerides, cetyl alcohol, corn starch, phenoxyethanol, carbomer, potassium cetyl phosphate, ethylhexylglycerin, hydrogenated palm glycerides, sodium [24] hydroxide, disodium EDTA, p‐anisic acid, fragrance [dipropylene glycol, methyldihydrojasmonate]
Horimukai [26] 2014	2e [Douhet]	Water, butylene glycol, squalane, xylitol, hydrogenated polydecene, pentaerythrityl tetraethylhexanoate, jojoba seed oil, isosteric acid, PEG‐60 glyceryl isostearate, dimethicone, PEG‐5 glyceryl stearate, behenyl alcohol, batyl alcohol, carbomer, potassium hydroxide, sodium metaphosphate, tocopherol, phenoxyethanol
Dissanayake [27] 2019	Locobase Repair	Petrolatum, aqua, paraffin, paraffinum liquidum, glycerin, sorbitan oleate, carnauba, cholesterol, ceramide 3, oleic acid, palmitic acid, carbomer, tromethamine
Ng [28] 2021	Cetaphil Restoraderm (PRO AD Derma) Skin Restoring Moisturizer	Aqua, glycerin, caprylic/capric triglyceride, helianthus annuus seed oil, pentylene glycol, butyrospermum parkii oil, cyclopentasiloxane, cetearyl alcohol, sorbitol, behenyl alcohol, glyceryl stearate, allantoin, arginine, caprylyl glycol, ceteareth‐20, cetyl alcohol, citric acid, dimethiconol, disodium EDTA, disodium ethylene dicocamide PEG‐15 disulfate, glyceryl stearate citrate, hydroxypalmitoyl sphinganine (ceramide), niacinamide, panthenol, sodium hyaluronate, sodium PCA, sodium polyacrylate, tocopheryl acetate
Ni Chaoimh [6] 2023	Aveeno Dermexa Fast & Long lasting balm	Glycerin, water, cetearyl alcohol, isocetyl alcohol, dimethicone, cetyl alcohol, oat kernel flour, benzyl alcohol, ethylhexylglycerin, sodium cetearyl sulfate, benzoic acid, dipotassium phosphate, potassium phosphate, palmitic acid, stearic acid, p‐anisic acid, caprylic/capric triglyceride, sodium hydroxide, oat kernel oil, ceramide 3, citric acid, oat kernel extract
Sugarman [29] 2009	EpiCeram to lesions	See Lowe [24]
	Cetaphil lotion non‐lesions	Water, glycerin, hydrogenated polyisobutene, ceteareth‐20, cetearyl alcohol, avocado oil, tocopheryl acetate (vitamin e), dimethicone, sodium levulinate, sodium anisate, caprylyl glycol, benzyl alcohol, panthenol (vitamin b5), stearoxytrimethylsilane, stearyl alcohol, citric acid, acrylates/c10‐30 alkyl acrylate crosspolymer
	Fluticasone propionate 0.05% lesions	Fluticasone propionate 0.5 mg in propylene glycol, mineral oil, cetostearyl alcohol, Ceteth‐20, isopropyl myristate, dibasic sodium phosphate, citric acid, purified water, methylparaben
	Cetaphil lotion non‐lesions	Water, glycerin, hydrogenated polyisobutene, ceteareth‐20, cetearyl alcohol, persea gratissima (avocado) oil, tocopheryl acetate (vitamin e), dimethicone, sodium levulinate, sodium anisate, caprylyl glycol, benzyl alcohol, panthenol (vitamin b5), stearoxytrimethylsilane, stearyl alcohol, citric acid, acrylates/c10‐30 alkyl acrylate crosspolymer
Somjorn [30] 2024	Linoleic acid, dexpanthenol, ceramide (Provamed Derma)	Water, shea butter, glycerin, petrolatum, niacinamide, hydrogenated polydecene, sunflower seed oil unsaponifiables, glyceryl stearate se, cyclopentasiloxane, sodium polyacrylate, cyclohexasiloxane, butylene glycol, jojoba seed oil, dimethicone, ceteareth‐25, tocopheryl acetate, sodium pca, hydroxyphenyl propamidobenzoic acid, allantoin, hydrogenated lecithin, biosaccharide gum‐2, sodium hyaluronate, phytosteryl/octyldodecyl lauroyl glutamate, licorice root extract, ceramide np, dipotassium glycyrrhizinate, coconut oil, pentylene glycol, ceteareth‐6, ammonium acryloyldimethyltaurate/vp copolymer, panthenol, phenoxyethanol, stearyl alcohol, chlorphenesin, bht, caprylic/capric triglyceride, disodium edta
	5% urea cream (NBD HEALTHCARE CO. LTD)	Urea (5%) in a cream base of butylene glycol, glyceryl stearate, disodium EDTA.
Gupta [31] 2023	Ceramide, cholesterol, fatty acid (AquaOat)	Purified water, light liquid paraffin, glycerin, butyrospermum parkii, cocoa seed butter, cetomacrogol 1000, cetyl alcohol, white soft paraffin, glyceryl stearate, peg‐100 stearate, dimethicone, polyacrylate‐13, phenoxyethanol, polyisobutene, oat kernel oil, oat meal extract, diazolidinyl urea, ethylhexylglycerin, polysorbate 20, sodium gluconate, sodium hyaluronate, iodopropynyl butylcarbamate, sodium lauroyl lactylate, ceramide 3, ceramide 6 ii, phytosphingosine, cholesterol, xanthan gum, carbomer, ceramide 1
	Paraffin based (Olesoft Max)	Light liquid paraffin IP 10.2%, white soft paraffin IP 13.2%, methyl paraben IP 0.114%, cream base
Chamlin [32] 2002	Ceramide, cholesterol, fatty acid (TriCeram)	Water, lanolin, peg‐20 methyl glucose sesquistearate, cetyl alcohol, ceramide, glycerine, petrolatum, dimethicone, curcumin, soybean sterol, linoleic acid, tocopheryl acetate, stearic acid, hyaluronic acid, carnosine, carbomer, tromethamine, propylene glycol, diazolidinyl urea, methyl/propylparaben
	Control	None, previous moisturizers described
Kircik [21]	EpiCeram	See above
2013	Eucerin	Water, petrolatum, mineral oil, ceresin, lanolin alcohol, phenoxyethanol, piroctone olamine
Danby [33] 2022	CeraVe	Aqua/water, glycerin, cetearyl alcohol, caprylic/capric triglyceride, cetyl alcohol, ceteareth‐20, petrolatum, dimethicone, phenoxyethanol, behentrimonium methosulfate, potassium phosphate, ethylhexylglycerin, sodium lauroyl lactylate, disodium ethylenediaminetetraacetic acid, dipotassium phosphate, ceramide NP, ceramide AP, phytosphingosine, cholesterol, xanthan gum, carbomer, sodium hyaluronate, tocopherol, ceramide EOP
	Zerobase	Liquid paraffin (11%), chlorocresol, white soft paraffin (10%), cetomacrogol, cetostearyl alcohol, phosphoric acid, sodium dihydrogen phosphate, purified water

The five infant studies of SC lipid therapies reported AD incidences from 5% to 37% versus AD incidences of 16%–46.4% at 12 months [6, 24, 25, 27, 28]. The AD incidence for a ceramide/fatty acid SC lipid therapy was 32.8%, significantly lower than the routine skin care control at 46.4% (p < 0.05) [6]. The AD incidence for SC lipid treatments and controls did not differ for the other 4 trials (Table 1) [24, 25, 27, 28]. Three trials performed skin prick tests for food/inhalation allergy sensitization and/or food allergies. Food allergy sensitization was 60.5% in the SC lipid‐based groups versus 46.1% in the no skin care control at 9 months, though differences were not significantly different [27]. At least one skin prick test was positive for 55.3% of a 38‐infant subgroup using the SC lipid therapy versus 22.9% of 35 no emollient controls, a statistically significant difference [28]. Of 119 infants on SC lipid therapy, 5 were skin test positive for food versus 4 of the 138 on the routine skin care control, indicating no difference [6]. The outcomes related to skin barrier integrity, including TEWL, skin hydration, skin pH, cohesion, and NMF levels, were generally not different for treatment versus control in the 5 infant studies. At 8 weeks, the skin pH was 5.46 for the SC lipid‐based treatment versus 4.98 for the control (glycerin, triglycerides lotion, as needed), a significant difference (p = 0.044) [25]. One study reported on bacterial infections, with comparable rates of 7.4% and 6.5% for SC lipid treatment and control, respectively [25].

Three of the 5 infant studies with SC lipid therapy reported treatment usage/adherence and yielded interesting results [6, 24, 25]. Lowe et al. specified 2X daily application but reported that 93% used them 3X weekly and 76% 5X weekly for SC‐lipid therapy versus the no emollient control levels of 4.8% routine use and 39% 3X weekly during the first 6 months [24]. McClanahan et al. instructed 1X daily application and reported adherence of 87%, 72.4%, and 66.7% at 2, 6, and 12 months. A glycerin/triglyceride product (Tables 1 and 2) was provided to the control group (as needed) and usage was 45.2%, 45.8%, and 45.5% at months 2, 6 and 12 [25]. Ni Chaoimh et al. specified 2X daily use of the SC‐lipid therapy and had 1X adherence of 89%, 89%, and 91.7% at weeks 2, 4, and 8 and 2X usage of 63.3%, 69.2%, and 73.1% at weeks 2, 4, and 8. The control group received routine skin care advice, and 68% used emollient < 4 days/week, and 19%, 17.5%, and 13.5% applied it ≥ 4 days/week at 2, 4, and 8 weeks [6].

An infant study of an oil‐in‐water emulsion versus petrolatum (as needed) facilitates comparison to the five SC lipid therapies trials (Table 1). Applied 1X daily from day 4 to week 32, the AD incidence of 32.2% for the oil‐in‐water emulsion is significantly lower than 47.4% for the control (p = 0.012) [26]. Skin hydration was higher for the emulsion (p < 0.05), but allergic sensitization and incidence of positive S. aureus (cheek) were comparable.

Four pediatric studies typically requested 2X daily use and reported AD severity using SCORAD after a treatment period of 1–6 months (Table 1) [29, 30, 31, 32]. Sugarman et al. compared an SC lipid treatment to a steroid (0.5% fluticasone propionate) in moderate–severe AD and found significant reductions in SCORAD, pruritus, and sleep disturbance [29]. The reduction for the steroid was significantly greater on day 14 but not on day 28. In a single group study (no placebo control), Chamlin examined an SC lipid treatment, 2X daily for 3 months, then once daily for 2 months, combined with topical steroid and/or tacrolimus, and found significant reductions in SCORAD to week 6, in TEWL to week 12, followed by an increase when application was reduced to once daily [32]. Skin barrier integrity improved to week 12 (more stripping to damage the barrier) with a decrease in integrity with 1X daily use. A comparison of an SC lipid‐based therapy with a paraffin‐based emollient 2X daily found significant reductions in SCORAD and TEWL and increases in skin hydration for both groups after 3 months but no differences between them [31]. Treatment of AD subjects with a ceramide, fatty acid, and dexpanthenol topical reduced the SCORAD more than a 5% urea treatment after 4 weeks (p < 0.05) [30]. The skin hydration increases and irritation incidences were comparable for both treatments.

One adult AD paired‐comparison trial of SC lipid‐based and paraffin‐based treatments found comparable reductions in TEWL of 15.9% and 14.5% and increases in skin hydration of 55% and 35%, respectively, over 4 weeks [34]. The other adult paired‐comparison trial compared two different SC lipid and paraffin‐based therapies. After 4 weeks of 2X daily application to dry, eczema‐prone skin, the treated sites were exposed to an irritant (sodium lauryl sulfate) applied under occlusion [33]. The SC lipid treated site had lower redness and TEWL than the paraffin site (p < 0.05). Skin hydration and skin barrier integrity, measured as cohesion by protein removal, were greater for the SC lipid therapy. The SC lipid treatment had increased lipid ester groups (from the triglyceride) on the skin surface but not within the inner SC layers [33].

4. Discussion

The findings from this review generally align with reports showing the benefits of emollients for reducing AD symptoms (i.e., SCORAD, pruritus) and increasing skin barrier integrity (i.e., TEWL). One SC lipid‐based therapy study suggests that it reduces the AD incidence in high‐risk infants when initiated soon after birth [6]; but others fail to show a definitive, i.e., statistically significant, benefit [24, 25, 27, 28]. However, SC lipid‐based therapies were generally well‐tolerated [24, 29, 32, 34]. Studies in both children and adults report minimal to no adverse effects, making them suitable for infants and individuals with sensitive or compromised skin [9, 24, 29, 32, 34].

The research on SC lipid treatments for AD prevention in infants is limited by small sample sizes that, in turn, reduce the statistical power and generalizability [9, 32, 33, 34]. Both SC lipid treatment adherence frequencies and emollient use by control subjects may have impacted the results in 3 studies. For example, Lowe et al. reported 3–5X weekly use of SC lipid therapy when 2X daily application was specified [24]. In addition, 39% in the “no emollient” control used it 3X weekly. Both effects could reduce the expected group differences in AD incidence and, therefore, the confidence in the study outcomes. Also reported were high drop‐out rates (36% before month 2) or study closure before complete enrollment could be achieved.

Another consideration for specific AD prevention approaches is the developmental status of the neonatal skin barrier itself. Healthy full‐term skin is functional, with a well‐formed SC and low TEWL at birth [35, 36]. The transition from the wet uterine environment prompts adaptative upregulation of processes for innate immunity and skin functioning in dry conditions. Skin hydration decreases rapidly then increases during the first two postnatal weeks before plateauing at 4 weeks. Adaptation upregulates the skin surface pH decrease and NMF production, prevents protease‐based desquamation, and increases antimicrobial function, markedly different from adult skin [37]. SC lipid composition/profiles varied over time during the first 3 months of life in non‐atopic infants, suggesting that maturation is ongoing [38]. Infant SC at 2 months of age had lower free sphingoid base levels and differing relative amounts before AD appeared, compared to infants without AD at 12 months [39]. In addition, infant AD prevention studies generally have not included normal, that is, non‐high‐risk AD infants to serve as a benchmark for normal skin adaptation. These factors may impact the response to emollient application. Conversely, topical treatments may influence the “normal” development.

5. Limitations

Specific features are notable as they emphasize the potential limitations of this review. The SC lipid‐based therapies (ceramides, cholesterol, fatty acids) varied in lipid composition (type, amount) and typically included additional ingredients (Table 2), precluding a meta‐analysis of multi‐study treatment efficacy. As noted in Table 2, many SC lipid therapies contained other ingredients, such as glycerin and/or petrolatum that impact the skin barrier, thereby confounding the delineation of the effects of the SC lipids on prevention of AD and skin barrier integrity outcomes. While the majority required one parent history of AD, others included all infants, thus reducing the probability of AD occurrence. Application frequencies differed and adherence was lower than expected, preventing cross‐study comparisons. Dissimilar infant demographics and outcome measures further complicate the ability to draw firm conclusions. The use of commercially available emollients (i.e., to clinicians, families) is appropriate but limits the generalizability of results due to variations in emollient composition.

6. Conclusions and Future Perspective

The topic of AD prevention is of great importance and notable controversy. Application of SC lipid‐based barrier therapies initiated shortly after birth is a potential strategy to reduce the incidence and disease burden and to facilitate prevention, delay the onset, and/or reduce the severity of AD in infants. However, the lack of robust statistical significance for SC lipid treatments raises questions about their true efficacy for AD prevention in infants. Current adult AD guidelines recommend use of moisturization [40]. A recent consensus suggested that SC lipid‐based therapy may mitigate AD occurrence and severity when used consistently from birth [9].

This review intended to ascertain knowledge gaps and to direct research, increase the efficacy of AD prevention strategies, and help mitigate controversies regarding emollients. It stimulated several questions that warrant investigation, namely: (1) Can SC lipid‐based therapies prevent AD in infants as a stand‐alone strategy? (2) Can SC lipid‐based therapies facilitate lower doses of traditional and/or acceptable AD treatments, for example, steroids, calcineurin inhibitors, methotrexate, dupilumab, JAK inhibitors? (3) What drives the AD phenotypes that result in early onset AD? [41](4) Is the skin maturation process different for infants who develop AD versus their non‐AD counterparts, where skin maturation is measured as skin barrier structure, homeostasis, microbiome, proteome, lipidome, and immune function? In addition, how does treatment with SC lipid therapies influence the “normal” “ideal” skin maturation process that leads to normal homeostasis? (5) What are the molecular‐level mechanisms that increase skin barrier integrity, measured as SC cohesion (i.e., response to tape stripping), skin penetration by known irritants (sodium lauryl sulfate) and inflammatory and immune responses? Are topically applied SC lipid ingredients incorporated into the SC to normalize the lipid bilayer structure? (7) Would an SC lipid AD prevention therapy need to vary with time to accommodate infant skin maturational changes and differences from adults?

Mechanistic studies in both high‐risk and non‐atopic infants, starting at birth and utilizing research designs, for example, within‐subject comparisons, that maximize outcomes are warranted. Determination of the “normal”, no‐treatment skin barrier maturation/adaptation for high‐risk and non‐atopic infants is key. Given the dynamic changes that occur in infant skin, frequent evaluation of key outcomes is recommended, including minimally invasive SC sampling for “omics” (protein biomarkers, lipids, microbiome, etc.), corneometry, and non‐invasive structural characterization (spectroscopy, confocal microscopy). Given the complexity of commercial products, studies would begin with relatively simple formulations, for example, containing only ceramides, cholesterol, and fatty acids matched to the lipid profile of infant SC at birth and over time. Research studies that address these questions, coupled with practical insights extracted from current clinical practice, will likely identify effective modalities to prevent, delay the onset, and decrease the incidence and severity, and facilitate updated treatment guidelines for individuals at risk or with AD.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.