Rahma & Lane 2022 — Skin barrier function in infants: update and outlook
This Pharmaceutics narrative review (Rahma at ITB Bandung / UCL School of Pharmacy; Lane at UCL School of Pharmacy) surveys what is known about the infant skin barrier with a primary focus on the diaper area, the safety and effectiveness of baby wipes, and the risk factors that predispose infants — especially preterm and low-birth-weight infants — to higher percutaneous absorption of topically applied chemicals. The paper contains no primary heavy-metal occurrence data; it is included in the Heavy Metal Index corpus as exposure-pathway infrastructure for any HMI work that needs to translate adult dermal-absorption inputs to infant skin (e.g., heavy metals in baby wipes, diaper creams, baby lotions, or sunscreens). The review reports nomenclature, quantitative differences between infant and adult skin, the consequences of diaper occlusion, baby-wipe formulation requirements, and the EMA / SCCS / FDA / RCPCH regulatory framing that governs paediatric topical ingredient selection.
Key numbers
- Nomenclature (Table 1, p. 2): Neonatal/newborn = first 4 weeks after birth; Infancy = whole first year; Full-term infants = born between 37th and 42nd week of gestation; Preterm infants = born before the 37th week; Low birth-weight infants = born below 2.5 kg.
- Stratum corneum (SC) thickness in infants is reported as ~30% thinner than adult and the viable epidermis as ~20% thinner (Table 2, p. 5, citing Stamatas et al. 2010 and the Hoeger and Enzmann 2002 prospective study). Corneocytes and keratinocytes are smaller; dermal papillae are more homogeneous; the dermal vascular network is extensive but disorganized; collagen fibre-bundle density is lower (Table 2).
- SC composition (text, p. 2): approximately 15% water, 15% lipids, 70% proteins; intercellular lipids are ceramides, cholesterol, and fatty acids in an ordered matrix. NMF, melanin, and water content are all lower at birth; water content increases through the first year (Table 2).
- Skin pH (text, pp. 6-7): newborn skin surface pH 6.6-7.5 at birth (Yosipovitch et al. 2000 and others); falls to 5-6 within the first few days; one prospective study (Giusti et al. 2001) reported a -1.31 pH-unit change on forehead between 3 days and 90 days; adult skin pH is 4-6.
- TEWL (text, pp. 8-9): normal adult TEWL 6-8 g/m²·h (Rogiers/EEMCO); preterm newborns up to 75 g/m²·h (Hammarlund & Sedin 1979) and are at higher risk of evaporative heat loss in low-humidity environments (<50%); Nikolovski et al. 2008 reported volar-forearm and dorsal-forearm TEWL significantly higher in healthy 3-12-month infants (n=50) than adults (p<0.01); older infants 8-24 months had TEWL similar to adults.
- Surface-area-to-body-weight ratio (text, p. 10): infant SA/BW is 2.3 times higher than adult; even higher in preterm and low-birth-weight infants (Renwick 1998, cited as ref 81).
- Cases of systemic absorption from topical exposure on preterm or compromised skin (text, pp. 9-10):
- Povidone iodine antiseptic on full-term newborns caused impaired thyroid function (West et al. 1981, citing ref 75); hypothyroidism reported in infants with spina bifida after topical povidone iodine (ref 76).
- Phenylephrine absorption increased in preterm newborns; rate decreased with postnatal age (ref 6).
- Preterm newborn skin reported up to 50-fold more permeable to alcohol and up to 1000-fold more permeable to salicylates than full-term newborn skin (West et al. 1981 / McCormack 1982, refs 3 and 11).
- Methylated-spirit cleansing of a 27-week-GA preterm newborn produced a post-mortem blood ethanol concentration of 3 mg/mL (Harpin & Rutter 1982, ref 10).
- 1% chlorhexidine in ethanol applied to umbilical cord of preterm newborns produced detectable plasma chlorhexidine; concentrations significantly higher than full-term newborns (p<0.001); preterm plasma chlorhexidine rose from 10 ng/mL at day 5 to 32 ng/mL at day 9 under repeated daily 9-day application (Aggett et al. 1981, ref 8). No systemic absorption observed for the powder formulation.
- Miconazole nitrate (0.25% ointment or 2% cream applied 5×/day for 7 days for diaper dermatitis): blood levels up to 3.8 ng/mL with the 0.25% ointment and 5-7 ng/mL with the 2% cream in infants with moderate-to-severe DD (Eichenfield & Bogen 2007, ref 147).
- Pharmacokinetic differences (Table 3, p. 10, healthy newborns vs adults): blood-brain barrier less developed; conjugation reactions lower; cytochrome P450 biotransformation lower; glomerular filtration lower; liver mass higher; plasma protein binding lower; water content per body weight higher. Biological half-lives in newborns are 3-9 times longer than adults and clearance rates are lower (Renwick 1998, ref 81). The pharmacokinetic and metabolic profile becomes comparable to adults within ~1 month after birth.
- Diaper-area-specific findings (Visscher et al. 2000, ref 47; n=31 full-term newborns, follow-up to 28 days): diapered (covered) area had significantly higher surface hydration and pH than the non-diapered control area above the waistband (p<0.05) at 14 days; at 28 days, the diaper-area pH remained higher (p<0.05) but hydration and water-sorption/desorption functions had normalized. Newborns urinate every 1-3 h on average, declining to ~7×/day by end of infancy (refs 85-86).
- Baby-wipes vs water-and-cloth clinical evidence summary (Table 4, p. 13):
- pH: comparable in two newborn studies (n=280 and n=44); significantly higher pH in water-and-cloth group in one infant study (n=15).
- Hydration: comparable in both studies that measured it (n=280 and n=44).
- TEWL: comparable in one newborn study (n=280); significantly lower TEWL in the baby-wipes group in another newborn study (n=44).
- Erythema: significantly lower erythema score in the baby-wipes group in 3/4 studies (preterm n=130; infants n=82; infant skin folds in n=102); IL-1α expression comparable (n=44).
- Baby-wipe formulation composition (Tables 5-7, pp. 14-16): cleansing lotion is >90% water; typical surfactant content ≤0.3% w/w (vs up to 5% in rinse-off cleansers). Most common preservatives in 2019 North American baby wipes (Hamann et al. 2019, ref 117, two-retailer average): sodium citrate / citric acid 69%; sodium benzoate 62%; phenoxyethanol 48%; iodopropyl butylcarbamate 23.5%; ethylhexylglycerin 6.5%. Common surfactants are predominantly non-ionic (coco-glucoside, glyceryl stearate, PEG-40 hydrogenated castor oil, polysorbate 20) at ≤0.5-2.0% w/w; sodium lauryl sulphate explicitly discouraged.
- Felter et al. 2017 (ref 148) safety-evaluation framework for diaper-area ingredients with diaper dermatitis (DD): assume 4-fold increase in dermal absorption in DD-affected skin for ingredients with normal-skin dermal absorption of 1-10%; 2-fold increase for ingredients with 10-50% absorption; for ingredients with >50% absorption, modification of exposure assessment is not required. For ingredients with unknown permeation data, an assumption of 100% dermal absorption is acknowledged as very conservative (text, pp. 18-19).
- Atopic dermatitis (AD) prevalence in children ≈20% (Telofski et al. 2012, ref 141); >90% of AD patients have early age of onset (≤5 years); hydrocortisone serum levels following 1% cream application order with AD severity: severe > moderate > mild (refs 153-154).
- EMA, SCCS, FDA, and RCPCH regulatory framing (text, pp. 13-19): EMA 2005 Reflection Paper on paediatric excipients; EMA Annex to Commission Guideline (SANTE-2017-11668) prohibits cyclodextrins as permeation-enhancing excipients in products for infants and children <2 yr; SCCS 2021 Notes of Guidance 11th Revision requires assessment of DD-impact on absorption for diaper-area products; US FDA / EMA / USP / Ph.Eur. specify purified-water quality for non-sterile baby-wipe water; RCPCH recommends emollient-containing cleansers for infants and children with AD; American Academy of Pediatrics restricts infant sunscreen use to areas not covered by clothes to minimize absorption (Paller et al. 2011, ref 66).
Methods (brief)
Narrative literature review. The authors state in the Introduction (p. 1) that to their knowledge the specific topic of infant skin barrier with focus on diaper-area regular use of disposable cleansing wipes had not been examined in detail previously, motivating this review. No systematic-review methodology is described — no search protocol, no inclusion/exclusion criteria, no PRISMA flow, and no quality-assessment instrument. References span 1928 (Schade & Marchionini’s original “acid mantle” paper) through 2021. The review draws together findings on skin structure (epidermis layers, dermal-epidermal junction, dermis), composition (NMF, lipids, melanin, water), function (cell turnover, hydration, immunological barrier, pH, photoprotection, sebaceous activity, TEWL), and percutaneous-absorption pathways (transappendageal vs transepidermal; intercellular vs transcellular). The Atopic-Dermatitis section uses the Hanifin & Rajka 1980 diagnostic criteria. The clinical-studies summary in Table 4 (n=44 to n=280 per study) is presented as a comparative tabulation rather than a meta-analysis; potential risk of bias (broad age ranges 6-24 months in some studies; one study did not disclose subject age) is acknowledged at the bottom of §6.1. Critical methodological caveats are stated explicitly: open-chamber TEWL probes are difficult to keep stable on moving infants; skin-pH interpretation is itself contested because pH is defined in aqueous solution and the SC contains lipids; and most reviewed clinical baby-wipe trials lacked validated and harmonized measurement protocols.
Implications
- Certification (HMTc): Provides the parameter inputs HMI needs to translate adult dermal-absorption assumptions to infants when setting heavy-metal limits in baby wipes and diaper-area products. The 2.3× SA/BW ratio, the 30% thinner SC, the 20% thinner viable epidermis, and especially the Felter et al. 2017 DD-modifier scheme (4× for 1-10% absorbed, 2× for 10-50% absorbed) are the operative inputs for any HMI exposure model that conditions on diaper dermatitis. The preterm-newborn salicylate observation (up to 1000-fold permeability vs full-term) is the limiting case that argues against extrapolating adult ABSd values to preterm or compromised skin without an explicit adjustment.
- Courses: Foundational paediatric-dermal-toxicology teaching reference. Useful as a paired reading with the ATSDR 2023 dermal-absorption guidance (which provides default ABSd / ABS_GI values for adults) and the Yun et al. 2022 in silico paediatric dermal model (which provides the maturation equations for adult-to-infant SC and epidermis thickness ratios). Together the three sources cover the inputs-to-equations-to-validation arc of paediatric dermal exposure modeling.
- App: Not directly relevant to ingredient
contamination_profiledata. The infant skin permeability factors and the Felter DD-modifier scheme are useful infrastructure for any per-product dermal-route risk estimator the HMI consumer app may eventually add for children’s personal-care products.
Wiki pages this source may touch
Verification notes
- Review article, narrative not systematic;
evidence_tier: B. The underlying primary studies cited (Hammarlund & Sedin 1979 TEWL; Visscher et al. 2000 diaper-area physiology; Stamatas et al. 2010 in vivo microstructure; Hoeger & Enzmann 2002 desquamation; Felter et al. 2017 DD safety-evaluation framework) are independently A-tier and should be located and ingested separately when HMI synthesis on infant dermal exposure needs primary measurements; this review’s value is the integration and the regulatory-framing summary, not the underlying numbers. metals: []is correct — the paper contains no heavy-metal occurrence data and no metal-specific permeability measurements. The systemic-absorption cases reviewed are pharmaceutical or antiseptic chemicals (povidone iodine, chlorhexidine, alcohol, salicylates, phenylephrine, miconazole, hydrocortisone), not metals.ingredients: []is correct — the paper does not discuss food ingredients; preservative and surfactant ingredients in baby wipes are formulation-level, not contamination-source, and are not in thewiki/ingredients/taxonomy.products: [baby-wipes, diaper-cream-zno, diaper-cream-non-zno, children-personal-care]: baby-wipes is the primary subject (Sections 6.1, 6.2, 7.1 of the paper); diaper-cream-zno and diaper-cream-non-zno cover §6.3 Post-Cleansing Barrier-Repair Creams (zinc oxide ointment and dexpanthenol 5%, respectively); children-personal-care is the umbrella context. Sunscreens are mentioned in passing (American Academy of Pediatrics recommendation) but not in enough depth to warrant baby-sunscreen-mineral / baby-sunscreen-chemical routing; declined.jurisdictions: [EU, UK, US]reflects the EMA / SCCS (EU), RCPCH (UK), and FDA / AAP (US) regulatory bodies the review references. Indonesia (author affiliation) and the WHO newborn-bathing recommendation are not jurisdiction-specific to the content of the paper.- Brand-firewall (Part 12): clean. The paper does not name commercial baby-wipe brands or rank manufacturers; it discusses preservative and surfactant ingredient classes and cites methylisothiazolinone-containing wipes (2005-2014 era) as a class without naming brands. The single “Procter & Gamble” reference is a market-research citation (ref 99) for percent-of-caregivers data, not a brand-ranking claim about product safety.
- Wiki/HMTc firewall (Part 2): clean. The review does not propose certification thresholds or comment on existing HMI / HMTc standards. The Felter et al. 2017 framework numbers are reported as the source’s regulatory framing (SCCS-adopted), not as HMI recommendations.
- Speciation flag: not applicable; no metals reported.
- Funding: Ministry of Finance, Republic of Indonesia studentship (Grant Ref S-1778/LPDP.4/2019) for Rahma. No declared conflicts of interest; no industry funding.
- Open access (CC BY 4.0); re-publishable with attribution under MDPI license terms.
- The paper-internal reference list assigns ref [78] to “Bernauer et al. 2021 - SCCS Notes of Guidance 11th Revision (SCCS/1628/21)” - this is the SCCS Notes of Guidance 11th Revision, not the 12th Revision that exists at
wiki/sources/sccs2023-notes-of-guidance-cosmetic-ingredients-v12.md. The two are sequential SCCS guidance versions and should not be conflated.
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