Update on the Use of Topical Agents in Neonates

Update on the Use of Topical Agents in Neonates
Marty O. Visscher, PhD
Topical agents include anything that touches the infant's skin. The skin is crucial to the way the infant
perceives and responds to the care environment and, therefore, in neurodevelopment. Psychological stress
negatively affects the barrier. The full-term infant has well-developed epidermal barrier despite spending
9 months being submerged in water. Vernix caseosa is a natural topical agent that facilitates stratum corneum
barrier development through protective and adaptive mechanisms. Its properties include hydration, wound
healing, antiinfection, and acid mantle development. The ontogeny of neonatal skin development and vernix
biology provide the basis for assisting barrier maturation in premature infants, treating compromised skin and
selecting topical agents. The published research on the effects of topical products on premature and damaged
neonatal skin is very limited, especially for adequately sized randomized controlled clinical trials. Health care
providers have keen interest and the skills to identify improved treatments through outcomes-based research.
Keywords: Skin barrier; Neonate, Topical agent; Stratum corneum; Compromised skin
Overview and Perspective
The article will review topical products in infants. Conceptually,
we define topical products in the broadest sense to include
anything that touches or interacts with infant skin. The skin is a
primary care interface vitally important in any patient-caregiver
interaction.1 The most recent information about skin structure,
development, and function will be discussed to generate the
context of topical treatments and products.
Touch is the first sense to develop in the infant. As a result,
the skin is an important element in the process of how the infant
perceives and reacts to the environment of care and, therefore,
in neonatal neurodevelopment. Examples of skin-based infant
interactions include skin-to-skin contact (kangaroo care), infant
massage, Newborn Individualized Developmental Care and
Assessment (NIDCAP), and tactile stimulation. Skin-to-skin
contact immediately after birth results in increased temperature
and blood glucose levels compared with swaddling next to the
mother.2 Skin-to-skin contact for 1 hour shortly after birth
impacted state organization and the time spent sleeping.3
Premature infants cared for with NIDCAP methods had
significantly better neurobehavioral function and more mature
neuronal fiber structure.4 In a longer-term study, infants
receiving NIDCAP had significantly better mother-child inter-
From the Skin Sciences Institute, Cincinnati Children's Hospital Medical
Center, Cincinnati, OH.
Address correspondence to Marty O. Visscher, PhD, The Skin Sciences
Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet
Avenue, Cincinnati, OH 45229. E-mail: Marty.Visscher@cchmc.org.
© 2009 Elsevier Inc. All rights reserved.
1527-3369/08/0901-0289$36.00/0
doi:10.1053/j.nainr.2008.12.010
action (cluster communication), better hearing/speech, and
lower behavior symptom scores.5 Tactile stimulation via
repeated stroking increased circulating lactate levels by 200%
in the neonatal rat model.6 These findings demonstrate the
critical role of simple infant-caregiver skin-based interactions on
the cognitive development of the infant.
Specific skin receptors are sensitive to mechanical stimuli
and are critical for survival. The signaling proteins involved in
this transduction are being identified.7 Psychological stress due
to environmental overcrowding is associated with a delay in
skin barrier recovery in mice, an effect attributed to increased
production of glucocorticoids.8 Psychological stress decreased
epidermal cell proliferation, adversely effected differentiation,
and decreased the size and density of corneodesmosomes, all of
which negatively impact skin barrier function.9 Stress decreased
antimicrobial peptides in the epidermis (animal model), an
effect that resulted in more severe skin infections.10
Skin Structure and Function
Human skin serves multiple functions including barrier (to
water loss, irritant exposure, light, etc), immunosurveillance,
infection control, sensation, structural support, and thermal
regulation (Table 1). The major skin layers are the epidermis,
dermis, and hypodermis (subcutaneous). Fig 1 shows a crosssection and the structures responsible for the functions. Two
layers comprise the dermis. The upper is the papillary layer,
contains capillary loops, and is loosely organized. The lower is
the reticular dermis composed of tightly packed collagen and
elastin with glycosaminoglycans, which provide mechanical
properties and elasticity. The epidermis includes the stratum
corneum (SC, outer) and the viable epidermis (Fig 2). An
understanding of SC structure and function is essential for being
Table 1. Skin Functions
Function
Barrier
Physical
(irritants)
Light
Immunologic
Resilient
foundation
Sensation
Tactile
discrimination
Thermal
regulation
Skin Structure
SC and epidermis
Melanocytes of the epidermis
Langerhans cells of the epidermis
Dermis
Sensory nerves in epidermis and
dermis
SC and sensory nerves
Eccrine sweat glands in dermis
Blood supply in dermis
Adipose fat in subcutaneous layer
(hypodermis)
able to select topical products. The SC is the main barrier to
water loss and penetration by outside agents. The viable
epidermis has four layers (top to bottom): clear (stratum
lucidum), granular (stratum granulosum), spinous (stratum
spinosum, nucleated cells), and basal (stratum basale, nucleated
cells). Two specialized dendritic cells are housed in the viable
epidermis. Langerhans cells (antigen-presenting cells) are part of
the immune system and serve as the line of defense if the SC
barrier is breached (Fig 2). The melanocytes (pigment cells)
reside in the basal layer and produce melanin, the pigment
responsible in part for inherent skin color. When the skin is
exposed to UV radiation, melanocytes are activated and transport
melanin to the nuclei of the epidermal cells to shield them and
protect the DNA. Skin tanning is the result of this process. The
pigmentary system is influenced by irritation and inflammation
and may respond by producing more pigment (hyperpigmentation) or by deactivation (resulting in hypopigmentation).
The function of the viable epidermis is to continually build
and replenish the SC. The cells “move up” from the basal layer
and transition to SC cells through a programmed process.
About 28 days is required for a cell to go from the basal layer
and be lost from the outer SC. The SC is made up of about 16
layers of flattened cells (corneocytes) joined together by
molecular “rivets” (aggregates of large molecules) called
desmosomes (insert in Fig 2). The SC is about half of the
thickness of a sheet of paper but incredibly strong. The process
of going from nucleated cells to SC corneocytes begins in the
upper spinous and granular cells with formation of the crosslinked cell envelope. Structures, called lamellar bodies, in the
spinous layer store lipids. In the upper granular layer (below
the SC), the lipids (cholesterol, fatty acids, ceramides) are
secreted from the lamellar bodies into the intercellular spaces
between the corneocytes to form a regular “brick (cells) and
mortar (lipids)” structure. The lipids form a regular ordered
bilayer structure, alternating with water, between the cells. By
design, the SC structure is difficult to penetrate from the
outside. It is the barrier to water loss but allows normal water
32
vapor from respiration to be released. The integrity of the SC is
measured in terms of the rate of transepidermal water loss
(TEWL). Normal skin has TEWL values of approximately 6 to
8 grams per square meter per hour, and higher rates indicate a
damaged barrier, poorly developed SC, or SC with fewer layers
than normal. The important goal of topical skin treatments is
to maintain or restore the SC barrier. A schematic of showing
normal and compromised SC barriers is shown in Fig 3.
Normal skin looses about one SC layer per day through the
process of desquamation where the connections between SC
cells degrade and release the cells to the environment. An
appropriate level of hydration is required for proper desquamation. Stratum corneum that is too dry will not desquamate
properly and results in large aggregates of cells, scales or dry
skin flakes. The protein filaggrin in the SC corneocytes is
converted to small water-binding amino acids called natural
moisturizing factor (NMF). Natural moisturizing factor is in
part responsible for maintaining the appropriate level of SC
hydration, and loss of NMF or disruption of the NMF
generation will result in low SC moisture. Excess hydration will
also cause barrier damage as will be discussed later.
Neonatal Skin Development
Birth marks are a significant environmental change for the
infant from a warm, sterile, and safe womb to a dry high-oxygen
environment with multiple organisms (bacteria) and demands
for self-sufficiency such as air breathing, enteral nutrition, waste
elimination, and maintenance of water balance. Neonatal skin
serves many functions at birth, including a barrier to water loss
and chemicals, temperature regulation, tactile discrimination,
Fig 1. Skin structures. A cross-section of the skin
shows the structures responsible for the functions.
The major skin layers are the epidermis, dermis, and
hypodermis (subcutaneous). The outermost layer,
the SC, is directly exposed to the environment. The
figure was provided by the National Institutes of
Health for use by the public and can be found at
http://media.nih.gov/imagebank/display_search.
VOLUME 9, NUMBER 1, www.nainr.com
Fig 2. Structure of the epidermis. The SC is the main barrier to water loss and penetration by outside agents.
The viable epidermis has four layers (top to bottom): clear, granular, spinous (nucleated cells), and basal
(nucleated cells). Two specialized dendritic cells are housed in the viable epidermis. Langerhans cells (antigenpresenting cells) are part of the immune system and serve as the line of defense if the SC barrier is breached.
infection control, immunosurveillance, antioxidation, and acid
mantle formation.
The Full-Term Infant
The full-term infant has well-developed epidermal barrier at
birth, despite spending 9 months being submerged in water. In
most cases, overhydration of the skin has a damaging effect, that
is, maceration, barrier disruption, and tissue injury. Transepidermal water loss (rate of respiratory water vapor loss, TEWL) is
very low at birth for full-term infant, equal to or lower than
adults, indicating a highly effective skin barrier.11,12 Within
minutes to hours after birth, skin hydration (moisture) varies
with body site (chest, back, forehead), time under the warmer,
and retention or removal of vernix caseosa.13,14 Hydration
decreases rapidly in the first day and then increases during the
first 2 weeks compared with constant values in the mother. This
change indicates that significant adaptive changes occur in the
upper SC.15 Newborn skin was significantly drier than the skin
of older infants (1, 2, and 6 months) and the mothers.16 Waterbinding ability increased during the first 14 days, denoting
changes in the water-handling processes within the SC. To
identify possible causes of low hydration, we measured the
NMF levels at birth and found it to be extremely low.17 They
were higher at 1 month but lower than levels in adults. Natural
moisturizing factor is water soluble and may be extracted from
the SC into the amniotic fluid. Alternatively, NMF generation
from filaggrin may be activited as part of the adaptation to dry
conditions. At birth, the full-term skin pH is relatively neutral,
NEWBORN
decreases significantly during the first 1 to 4 days, and
continues to drop during the first 3 months.12,15,18 The
antimicrobial protein lysozyme was found in newborn SC at
levels five times higher than adults. Lysozyme activity was not
altered with routine bathing.19
Vernix Caseosa: Natural Topical
Treatment
The question remains: How does the full-term infant develop
an excellent barrier while in water? During the last trimester,
vernix caseosa begins to coat the skin from head to toe and back
to front and may facilitate SC barrier development.14 Vernix is a
complex mixture of 80% water, 10% protein, and 10% lipids,
with corneocytes embedded in a lipid matrix.20 The remarkably
high water is associated with the cells. Vernix formation is
believed to be under hormonal control during gestation, with
lipids generated by the sebaceous gland and cells from the hair
follicle. It is “extruded” onto the interfollicular epidermis to
cover the whole surface.21 Presumably, vernix forms a hydrophobic surface, thereby protecting the epidermis from exposure
to water, and creates conditions under which the cornification
and formation of the SC can occur. Vernix contains antimicrobials; for example, lysozyme, lactoferrin, and the antiinfective
properties have been demonstrated by several researchers.22-25
Vernix treatment of adult volar skin increased the SC waterbinding capacity.26 Native vernix treatment of SC wounds (tape
stripped skin) assisted barrier repair relative to controls and
& INFANT NURSING REVIEWS, MARCH 2009
33
Premature Infant Skin Development
Fig 3. The development of the SC occurs during the
last trimester of gestation and is relatively well formed
on average by week 34 to 35. At 23 weeks, the SC is
nearly absent and TEWL values are 75 grams per
square meter per hour. By week 26, a few cornified
layers have formed (TEWL of approximately 45 grams
per square meter per hour). At 29 weeks, the TEWL is
17 grams per square meter per hour and markedly
higher than values of 5 to 6 grams per square meter
per hour observed in the full-term infant.
demonstrated wound healing properties.27 In some settings,
vernix is removed immediately after birth. The role of vernix in
neonatal skin adaptation was assessed by comparing the effects
of vernix retention vs removal in parallel groups of full-term
infants at delivery. Vernix retention resulted in significantly
higher skin hydration 24 hours after birth.14 Skin pH values
were lower in the vernix-retained group, suggesting that vernix
facilitates the development of the acid mantle. Treatment of SC
wounds (created by repeatedly tape stripping adult forearm skin
to remove SC layers) with vernix assisted barrier repair relative to
controls.27,28 In model systems, vernix enhanced SC formation
without increasing epidermal thickness.29 Films of vernix
impeded the penetration of the exogenous enzyme chymotrypsin (found in meconium, similar proteolytic enzymes
present in feces) but maintained the activity of native enzymes
(necessary for epidermal development) in vitro.29
Overall, vernix facilitates SC barrier development in the
normal full-term infant through a variety of protective and
adaptive mechanisms. The findings provide support for the
practice of vernix retention (rather than removal) at birth. The
World Health Organization recommends waiting for at least 6
hours before bathing newborn infants in part to facilitate the
positive effects of residual vernix.
34
Unlike that of the full-term baby, the dermis of the premature
infant is not fully formed and deficient of structural proteins. As
a result, the mechanical properties are poor and the skin is easily
torn. The preterm epidermis is markedly thinner, and the SC is
poorly formed in contrast to the thick fully developed SC of the
full-term neonate. The SC structural integrity is directly related
to gestational age at birth, and rapid barrier development occurs
from weeks 24 to 34. Very low-birth-weight infants are at
greatest risk for skin damage during the early days of life. At
23 weeks, the SC is nearly absent with TEWL of 75 grams per
square meter per hour (Fig 3).30 By week 26, a few cornified
layers have formed (TEWL of approximately 45 grams per
square meter per hour). The very premature infant has,
essentially, a wounded skin surface.31,32 At 29 weeks, the
TEWL is 17 grams per square meter per hour and markedly
higher than the values of 5 to 6 grams per square meter per hour
observed in the full-term infant. Around weeks 34 to 35, the
barrier is relatively well formed. Infants born prematurely (ie,
b28 weeks) do not have the covering of vernix.
Poor SC integrity puts the premature infant at risk for high
water loss, electrolyte imbalance, thermal instability and
increased exposure to environmental irritants and infectious
agents due to increased permeability. After birth, the barrier
continues to develop, but even after 1 month, TEWL is
significantly higher than in normal full-term infants.33 Further
impairment of barrier function in premature infants was
indicated by significantly higher values of skin hydration, and
infants less than 30 weeks gestation have significantly higher
values of skin hydration than those older than 30 weeks as a
result of higher rates of water being lost through the skin.34 By
day 5, the skin hydration was significantly lower for infants less
than 27 weeks' gestational age, indicating rapid barrier
development. The humidity of the environment influences the
rate and quality of SC barrier maturation. Exposure to low
humidity (10% relative humidity [RH], animal model) resulted
in a decrease in SC hydration and an increase in epidermal DNA
synthesis. This observation suggests that low hydration triggers
cell proliferation.35 Clinically, very premature infants frequently
exhibit an abnormal pattern of desquamation several weeks
after birth, indicative of a hyperproliferative SC. Humidity
affects the degradation of epidermal filaggrin to NMF that binds
water in the SC.36 Without NMF, the SC is dry, does not
desquamate properly, and has poor water-holding capacity. At
birth (animal model), filaggrin degradation occurred at 80% to
95% humidity but not at high (100% RH) or low humidities,
suggesting that NMF generation depends upon ambient water
activity.37 Natural moisturizing factor levels are likely to be very
low under the conditions of rapid SC development such as for
premature infants in low humidity.
Skin Occlusion
Appropriate SC hydration is necessary for effective skin
function, for example, to allow sufficient plasticity and
flexibility during movement, to prevent cracking, and for
VOLUME 9, NUMBER 1, www.nainr.com
desquamation.38,39 However, prolonged exposure to water
causes skin maceration, barrier breakdown, and dermatoses,
including inflammation, irritation, and urticaria.40-45 Water
exposure caused SC abnormalities, including disruption of the
intercellular lipid bilayers, degradation of the desmosomes, and
creation of amorphous regions within the lipids, as illustrated
in Fig 3.46
Hydration causes the SC corneocytes to swell, increases the
fluidity of the lipids, and enhances molecular transport to
increase permeability to exogenous materials.47,48 Occlusion of
the skin surface can occur from any material that does not allow
sufficient water to pass through it, including diapers, certain
tapes, thick layers of topical products, and devices such as
braces, casts, and splints.49 Water builds up under the material
and causes SC hydration to increase and barrier damage to
occur, as shown in Fig 4.
Topical Treatments for Infants
The biology of infant skin development and maturation
provides the clues for identifying strategies for treating
compromised skin. Vernix may be the “ideal” topical treatment,
as some suggest, for infants and adults.50,51 Infants born
prematurely (ie, b28 weeks) are missing protective covering of
vernix. In the broadest sense of “topical treatments” as anything
that interacts with the outer skin surface, specific strategies will
be discussed.
Treatments for Barrier Maturation
Environmental conditions Humidified isolettes have been used
to mitigate the high water loss in premature infants. Extremely
low-birth-weight infants needed lower fluids and had improved
electrolyte balance.52 Humidity is used routinely with levels
adjusted to manage fluid loss, temperature, and so on to
ensure that overhumidification does not cause bacterial
contamination.53 A 2006 study among infants of 23 to
27 weeks' gestational age showed that the SC barrier developed
more rapidly for the neonates in isolettes at 50% RH compared
with infants at 75% RH.54
Films Transparent semipermeable dressings (eg, Tegaderm; 3M,
St. Paul, MN) have been used to control water loss in premature
infants. Tegaderm dressing was applied to large body surface
areas on infants of 24 to 26 weeks' gestational age, and daily
fluid intake, serum sodium levels, and weight loss were
significantly lower compared with infants who had not been
treated.55 Transepidermal water loss was also reduced, indicating that the film had assisted in barrier maturation. In infants
less than 32 weeks' gestational age, TEWL decreased for a skin
site treated with a semipermeable dressing relative to the
untreated control, and counts of gram-negative bacilli were
comparable.56 Application of nonadhesive semipermeable films
to infants less than 32 weeks' gestational age significantly
reduced water loss and improved barrier maturation compared
with the contralateral untreated control site.57 For infants of
770 to 1450 grams, those treated with a dressing required less
current for thermal control and had lower TEWL than the
untreated control group.58
Barrier creams The effects of whole-body treatment topical
petrolatum-based “skin barrier creams” in premature infants
have been reported in various settings. Infants (n = 32, 29–36
weeks) received a cream (containing petrolatum, mineral oil,
Fig 4. Effects of skin occlusion. Occlusive treatments prevent water loss, allow water to build up resulting in
damage to the SC barrier, and allow increased penetration.
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& INFANT NURSING REVIEWS, MARCH 2009
35
Table 2. Skin Protective Active Ingredients Under the FDA Final Monograph
Ingredient
Allantoin
Aluminum hydroxide gel
Calamine
Cocoa butter
Cod liver oil
Colloidal oatmeal
Dimethicone
Glycerin
Hard fat
Kaolin
Lanolin
Mineral oil
Petrolatum
Sodium bicarbonate
Topical starch
White petrolatum
Zinc acetate
Zinc carbonate
Zinc oxide
Allowed Amounts (%)
Other Label Claims
0.5–2
0.15–5
1–25
50–100
5–13.56 not to exceed 10 000 USP units of
vitamin A, and 400 USP units cholecalciferol
0.007 (minimum) or 0.003 (minimum)
combined with mineral oil
1–30
20–45
50–100
4–20
12.5–50
15.5 with other skin protectants for diaper rash
50–100 and 30–35 with colloidal oatmeal
30–100
Na
10–98
30–100
0.1–2
0.2–2
1–25
⁎, #
⁎, #
⁎
#
#
⁎, #
⁎, #
⁎, #
⁎, #
⁎, #
Those with asterisk (⁎) may also claim “temporarily protects minor cute, scrapes, and burns,” and those with pound sign (#) can state “helps prevent and
temporarily protects and helps relieve chaffed, chapped, or cracked skin. USP = United States Pharmacopeia.
mineral wax, wool wax alcohol, water) or no treatment twice a
day for 12 days. Transepidermal water loss decreased for both
groups, but skin condition was better for the treatment group vs
the controls whose condition worsened.59 A second study
among 60 babies (b33 weeks; mean, 29 weeks) who were
treated with a similar formulation twice a day showed lower
TEWL, less dermatitis, lower skin colonization, and fewer
positive blood and cerebrospinal fluid cultures.60 A group of
investigators from Association of Women’s Health Obstetric and
Neonatal Nurses (AWHONN) and National Association of
Neonatal Nurses (NANN) conducted a major research project to
review the scientific literature and develop an evidence-based
practice guideline for all aspects of skin care for neonates.61
Based on the available research, the guideline recommended
twice-daily whole-body application of a barrier cream (eg,
Aquaphor (Beiersdorf AG, Hamburg, Germany) containing
petrolatum, mineral oil, mineral wax, wool wax alcohol, water).
To test the effectiveness of the practices on outcome, that is, skin
condition and compliance, they enrolled 51 units across the
country to participate. The research plan involved education in
the specific practices and evaluation methods.62 A total of 2820
infants (mean, 2100 grams; range, 500–5700 grams) were
included. The skin condition score decreased, and the
frequency of compliance with the guideline increased as a
result (preguideline vs postguideline comparison).63 The skin
scores reflected the combination of practices, and the effect of
the topical treatment alone could not be determined. Infection
rates were not formally evaluated.
Fig 5. A, Normal and damaged SC. The SC cells are joined by molecular “rivets” called desmosomes. The
lipid bilayer structure can be compromised, for example, from water exposure. Irritants can more easily
penetrate a damaged barrier. Premature infant skin has fewer SC layers and, therefore, increased permeability.
B, Effects of the diaper environment. The figure illustrates how factors of the “diaper environment” impact
skin barrier structure, function, and response. The humid environment leads to overhydration of the SC
causing disruption of the lipid bilayer structure. When the SC integrity is damaged, irritants and
microorganisms can penetrate and reach the Langerhans cells and epidermis. Fecal enzymes disrupt the SC
integrity by degrading proteins, providing another mechanism for barrier breach. Penetrants/irritants interact
with keratinocytes, stimulating them to release cytokines. Cytokines act on the vasculature of the dermis,
resulting in inflammation.
36
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& INFANT NURSING REVIEWS, MARCH 2009
37
Another multicenter (n = 54 neonatal intensive care units)
trial in 1191 younger premature infants (mean, 26.2 weeks)
compared twice-daily treatment with an ointment (petrolatum,
mineral oil, mineral wax, wool wax alcohol) with no treatment
among parallel groups to isolate the effects of the ointment.64
The nosocomial infection rates were not different for the total
group but were significantly higher for the treatment vs control
among infants from 501 to 750 grams. The sepsis was caused
by coagulase negative in more than 60% of the cases. This
finding was not anticipated, given the favorable results of
others. However, the infants from this multicenter trial had a
mean estimated gestational age (EGA) of 26 weeks vs the mean
of 29 weeks in previous reports. Transepidermal water loss was
not measured, but TEWL for a 26-week infant would be about
45 grams per square meter per hour vs 15 to 17 grams per
square meter per hour for a 29-week infant and represents a
substantial difference in barrier maturation and integrity.30,34
Product doses may have differed between the trials. Levels of
0.5 to 2.0 grams per square centimeter can be quite
occlusive.65 Normal adult volar forearm skin was occluded
with plastic film for 5 days.66 Significant increases in total
average microbial counts were seen on day 5, and coagulasenegative staphylococci (well tolerated in healthy adults) were
present in the greatest amounts (63%). One possible explanation
for the increased incidence of nosocomial infection in the extremely
low-birth-weight infants is that the treatment was sufficiently
occlusive to delay barrier maturation and to allow the growth of
coagulase-negative Staphylococcus. In another report, an increase
in systemic candidiasis was found in extremely low-birthweight infants (n = 40) treated with topical petrolatum.67 Until
the cause of the increased infection rates is understood, the use
of petrolatum-based low-water ointments in very premature
infants will remain controversial. A Cochrane review published
in 2004 recommended that they not be used on premature
infants because of the risk of infection.68 It is important to
remember that a petroleum-based cream is a barrier to stool,
but it does not allow the skin to breathe and remove toxins
because it blocks the pores.
Fig 6. Diaper skin care. The management of diaper skin condition is outlined.
38
VOLUME 9, NUMBER 1, www.nainr.com
Topical oils Daily infant massage with oils is common practice in
many societies. A study of family attitudes in Bangladesh showed
that massage begins within the first 3 days in premature and fullterm infants and is believed to prevent infections and loss of
heat.69 Mustard oil is commonly used, but controlled studies
showed that it delayed SC barrier maturation and caused skin
damage, whereas sunflower seed oil improved the barrier.70 The
application of sunflower seed oil to the skin surface of premature
infants less than 33 weeks' gestational age at birth reduced the
incidence of nosocomial blood infections by 41% in developing
countries.71 In the same study, infants less than 1250 grams who
were treated with Aquaphor had a reduced incidence (71%) of
sepsis. A controlled trial among 457 infants with 33 weeks'
gestational age or less in the special care nursery of Dhaka Shishu
Hospital, Bangladesh, evaluated the effects of daily treatment
with sunflower seed oil (n = 159) or Aquaphor (n = 157) vs a no
treatment (n = 181) on mortality rates.72 Rates were significantly
reduced for both treatments (26% sunflower seed oil, 32%
Aquaphor), and the results continue to support these treatments
for use in developing countries. A controlled trial among 173
infants of 25 to 36 weeks' gestational age compared the effect on
skin of two topical treatments vs no treatment control for 4
weeks of twice-daily application.73 One treatment was a mixture
of olive oil (30%) and lanolin (70%), and the other was
Bepanthen (Bayer Health Care, Leverkusen, Germany), a waterin-oil cream containing dexpanthenol and phenoxyethanol. The
composition of the cream is not disclosed by the manufacturer.
The infants treated with olive oil/lanolin had significantly less
skin dermatitis (dryness, erythema) than either Bepanthen or no
treatment, and no difference in infection rates was reported
among the groups. The mechanism by which these oils enhance
SC barrier formation continues to be investigated, particularly in
terms of the uptake of certain components into the SC lipid
architecture and in the optimum mixture of lipids.74–76
Topical Treatment of Skin Compromise
The presence of minor skin damage increases the likelihood
of further injury in the high-risk neonate, and prevention/early
intervention has been the focus of health care providers who
care for them. The published research on the effects of topical
products on damaged skin in neonates is very limited, especially
for adequately sized randomized controlled clinical trials. The
task becomes selecting one of the appropriate and effective
products. Consideration of the regulatory guidelines for skin
care products may be helpful in making those selections.
Regulatory Guidance for Skin Products
Topical interventions include “barrier creams,” “barriers,”
“skin pastes,” “skin protectants,” “moisture barriers,” and
“moisturizers.” Many are marketed under the Food and Drug
Administration (FDA) Final Monograph entitled Skin Protectant
Drug Products for Over-the-Counter Human Use.77 Skin protectants “provide temporary relief from harmful or annoying
stimuli.” The “active ingredients” and their allowed levels are
NEWBORN
listed in Table 2. Those with asterisk (⁎) may also claim
“temporarily protects minor cute, scrapes, and burns,” and
those with pound sign (#) can state “helps prevent and
temporarily protects and helps relieve chaffed, chapped, or
cracked skin.” The label must also state the following: for
external use only, do not use on (deep puncture wounds,
serious burns, animal bites), do not get into eyes, keep away
from face and mouth to avoid breathing it, stop use/ask doctor if
condition worsens or symptoms last more than 7 days or clear
and return. Unlike prescription drugs and other categories of OTC
drugs, the FDA does not require randomized controlled clinical trials
before approval and to demonstrate effectiveness. Therefore, one
should be aware that effectiveness has not been shown in
controlled clinical trials. The FDA does not review or approve
cosmetic claims, such as “soothes” or “dryness.” The paucity of
data can be attributed in part to the fact that products can be
marketed without demonstrated efficacy.
Treatment of Diaper Dermatitis
Etiology Skin damage in the diaper area is the result of several
factors in the “diaper environment.” They include increased skin
hydration, contact with skin irritants (urine, feces, enzymes in
feces, bile salts, etc), mechanical friction (skin to skin, diaper to
skin), skin pH, nutritional status or diet (fecal composition),
gestational age (barrier maturation status), use of antibiotic
therapy, presence of diarrhea, and medical condition.48,78-83
Diapered skin pH was higher than a nondiapered control site in
neonates and older infants, and increased pH was related to the
effects of occlusion and increased skin permeability.18,84,85
Higher skin pH was associated with higher skin hydration
(wetness) and diaper rash scores.81 Irritants cause skin damage
by disrupting the lipid bilayers of the SC, thereby allowing
penetration into the viable epidermis. Irritants (eg, sodium lauryl
sulfate (SLS)) increase keratinocyte proliferation and alter
metabolism and differentiation.86,87 In response, the epidermis
up-regulates SC formation, resulting in a defective structure,
aberrant water handling, and inadequate desquamation.88-93
Perineal skin excoriation can occur in conditions where
pancreatic enzymes are not deactivated in the colon.94,95 When
a mixture of pancreatic enzymes and bile salts was applied under
occlusion, erythema, blood flow, skin pH, and TEWL all
increased.96 Patients who get supplemental digestive enzymes
(eg, for metabolic diseases) are at risk for skin breakdown because
the unabsorbed enzymes can be excreted in the feces and break
down the SC proteins.97 Infants with neonatal abstinence
syndrome often have diarrhea and can have severe diaper skin
excoriation.98–100 Figs 5A and B illustrate the processes involved
in diaper skin breakdown.
Strategy The approach for resolving diaper breakdown is based
on minimizing or eliminating the causes and intervening early.
Fig 6 shows the aspects of diaper skin care.
When damage is noted, the presence of infection (eg, yeast,
bacterial) must first be determined. Rash due to Candida
& INFANT NURSING REVIEWS, MARCH 2009
39
albicans can include bright red color, patchy pattern (areas may
be surrounded by scales), and pustules. Topical antifungal
agents are the treatment of choice and include nystatin,
miconazole, clotrimazole, and ciclopirox for infants.101 Nystatin is prescribed most frequently by pediatricians.102 Combinations of antifungals and mid-high potency corticosteroids are
not recommended because they can cause skin atrophy and
penetrate more easily under the occlusive diaper conditions.102
A placebo-controlled trial of subjects with acute rash showed
significantly lower rash scores for treatment with 0.25%
miconazole nitrate in zinc oxide/petrolatum than the controls
with the zinc oxide/petrolatum vehicle, and subjects with
moderate to severe rash had the greatest improvement.103 A
separate safety study showed low systemic absorption of
miconazole nitrate in infants.104 Treatment of bacterial infections is based on the organisms involved.
The goal for managing diaper skin breakdown is to somehow
allow for healing despite the continuing exposure to the
Fig 7. Algorithm for diaper dermatitis. An algorithm
for the management and selection of treatments for
diaper dermatitis is shown.
40
Fig 8. Skin evaluation. The effects of treatment plans
can be monitored by the evaluating the damage (ie,
erythema, rash, dryness, etc) in terms of area of
coverage and severity.
offending agents. Ideally, topical treatments (a) provide a
semipermeable “film” or “layer” over the damaged skin to allow
SC barrier repair, (b) provide a physical shield between the skin
and the irritants, (c) remain in place on the skin (not removed
by feces), and (d) allow for ease of skin cleansing (minimize
stripping). Complete occlusion of damaged skin can cause delay
in healing. Skin repair occurs more quickly when treated with
barriers, creams, or films that are semipermeable to water
vapor.105,106 An algorithm for the management and selection of
treatments is shown in Fig 7. Once a plan is in place, it can be
helpful to monitor the effects by noting the area of involvement
(% area covered) and severity of damage (faint erythema,
definite redness, intense redness, rash, bleeding, etc). For
example, Fig 8 shows a scheme for evaluating erythema.
Topical treatment The diaper rash creams and moisture
barriers usually contain a skin protectant (ie, one of the “active
ingredients” covered by the FDA monograph), commonly zinc
oxide, petrolatum, or dimethicone alone or in combination. The
published data on topical protectants are virtually nonexistent
for adequate controlled trials in infants, especially the high-risk
population. In vivo studies (usually adults) on treatment irritant
dermatitis with barrier creams have shown mixed results, with
skin improvement in some and worsening in others.107
Hoggarth et al108 evaluated six commercially available products
for irritant protection, prevention of maceration, and protection
against topical agents. However, the test applied them once a
day and then exposed the skin to irritant (sodium lauryl sulfate
surfactant) for 24 hours daily for 4 days. Patches are completely
occlusive and probably caused the irritant to pass through the
barrier cream as well as through the SC.
Common diaper rash creams, moisture barriers, and their
ingredients are shown in Table 3. The “skin protectant” is in
bold and must be at FDA monograph level to make the claim.
The others are considered to be “inactive,” and US regulations
require them to be listed in the order of amount, unless they are
at 1% or less where they can be in any order. These ingredients
give the products the features of thickness, ease of application,
and so on, but they also function to provide uniformity. As an
example, Table 4 lists the function of each ingredient in two of
the products.
VOLUME 9, NUMBER 1, www.nainr.com
Table 3. Diaper Rash and Moisture Barrier Creams and Their Ingredients
Name
Desitin (Pfizer, Inc., New York, NY)
Desitin Creamy
(Pfizer, Inc.)
Desitin Clear All Purpose
(Pfizer, Inc.)
A&D Ointment Original (Schering
Plough, Kenilworth, NJ)
A&D Diaper Rash Cream with Zinc
Oxide (Schering Plough)
Triple Paste (Sommers Laboratories,
Inc., Collegeville, PA)
Boudreaux's Butt Paste (Blairex,
Columbus, IN)
Canus Li'l Goat's Milk 40% Zinc
Oxide Ointment (Canus,
Waitsfield, VT)
Aquaphor (Beiersdorf)
Balmex (Chattem, Inc.,
Chattanooga, TN)
Mustela Bebe Vitamin Barrier
Cream (Laboratories
Expanscience, Paris, France)
Triple paste medicated ointment
(Sommers Laboratories, Inc.)
Aveeno baby soothing relief Diaper
Rash Cream (Johnson &
Johnson Consumer Companies,
Inc., New Brunswick, NJ)
Burt's Bees Baby Bee (Burt's Bees,
Durham, NC)
Mustela Dermo-Pediatrics Stelactiv
Diaper Rash Cream (Laboratories
Expanscience)
Palmer's Bottom Butter (E.T.
Browne Drug Company, Inc.,
Edgewood Cliffs, NJ)
Jason Natural Cosmetics Earth's
Best Organic Diaper Relief
Ointment, Aloe Vera and
Vitamin E (The Hain Celestial
Group, Inc., Melville, NY)
Ingredient List
Zinc oxide (40%), BHA, cod liver oil, fragrance, lanolin, methylparaben, petrolatum,
talc, and water
Zinc oxide (10%), Aloe barbadensis leaf juice, cyclomethicone, dimethicone, fragrance,
methylparaben, microcrystalline wax, mineral oil, propylparaben, purified water,
sodium borate, sorbitan sesquioleate, vitamin E, white petrolatum, and white wax
White petrolatum (60.4%), cholecalciferol, cocoa butter, fragrance, light mineral oil,
mineral oil, modified lanolin, paraffin, sodium pyruvate, sunflower seed oil, vitamin A
palmitate, vitamin E (DL-alpha tocopherol and DL-alpha tocopheryl acetate)
Petrolatum (53.4%), lanolin (15.5%), cod liver oil (contains vitamin A and
vitamin D), fragrance, light mineral oil, microcrystalline wax, paraffin
Dimethicone (1%), zinc oxide (10%), aloe barbadensis extract, benzyl alcohol,
coconut oil, cod liver oil (contains vitamin A and vitamin D), fragrance, glyceryl oleate,
light mineral oil, ozokerite, paraffin, propylene glycol, sorbitol, synthetic beeswax, water
Zinc oxide, lanolin, and beeswax. Triple paste is fragrance free and contains no
added preservatives
Zinc oxide (16%), boric acid, castor oil, mineral oil, paraffin, Peruvian balsam,
petrolatum
Zinc oxide (40%), petrolatum, goats milk (fresh), mineral oil, emulsifying wax NF,
fragrance (parfum), beeswax, propylene glycol, diazolidinyl urea, methylparaben,
propylparaben
Petrolatum, mineral oil, ceresin, lanolin alcohol, panthenol, glycerin, bisabolol
White petrolatum (51%), cyclomethicone, dimethicone, mineral oil, polyethylene,
silica
Zinc oxide (10%), water, mineral oil, propylene glycol dioctanoate, methyl glucose
dioleate, titanium dioxide, PEG 45 docecyl glycol copolymer, glycerin, ceresin, ethyl
linoleate, Shea butter, PEG 8, panthenol, potassium sorbate, fragrance, magnesium
sulfate, methylparaben, caprylyl glycol, propylparaben, sodium polyacrylate
Zinc oxide (12.8%), white petrolatum, corn starch, anhydrous lanolin, stearyl
alcohol, beeswax, bisabolol, cholesterol, water, glycerin, oat kernel extract (Avena
sativa), polysorbate 80
Zinc oxide (13%), A sativa (oat) kernel extract, beeswax, benzoic acid, dimethicone,
Epilobium angustifolium flower/leaf/stem extract, glycerin, methylparaben,
microcrystalline wax, mineral oil, Oenothera biennis (evening primrose) seed extract,
potassium hydroxide, propylparaben, sorbitan sesquioleate, synthetic beeswax, water
Zinc oxide, sweet almond oil, beeswax, tocopheryl acetate, tocopherol (vitamin E),
jojoba oil, lavender oil, retinyl palmitate (vitamin A), extract of rosemary, lavender,
calendula, chamomile, rose petal, comfrey root
Zinc oxide (10%), water, mineral oil, propylene glycol diethylhexanoate, methyl
glucose dioleate, titanium dioxide, PEG 45 docecyl glycol copolymer, glycerin, ceresin,
panthenol, Lupinus albus seed extract, PEG 8, Butyrospermum parkii fruit (Shea butter),
ethyl linoleate, potassium sorbate, caprylyl glycol, methylparaben, magnesium sulfate,
propylparaben, sodium polyacrylate
Petrolatum (30%), dimethicone (1%), water, mineral oil, aluminum starch
octenylsuccinate, PEG 30 dipolyhydroxystearate, stearyl alcohol, Theobroma cacao
(cocoa) seed butter, microcrystalline wax, fragrance, Zea mays (corn) oil, retinyl
palmitate, cholecalciferol, panthenol, beta carotene, vegetable oil, isopropyl myristate,
propylene glycol, methylparaben, propylparaben, diazolidinyl urea
Zinc Oxide (12%), lavender extract, caprylic/capric triglycerides, C12 15 alkyl benzoate,
sorbitan isostearate, sorbitan sesquioleate, water (purified), ethylhexyl palmitate, calcium
starch octenylsuccinate, ethyl macadamiate, stearalkonium hectorite, glyceryl laurate, oat
kernel oil, tocopheryl acetate (vitamin E), beta glucan, chamomile flower extract (certified
organic), marigold flower extract (certified organic), propylene carbonate, magnesium
sulfate, benzyl alcohol, potassium sorbate, sodium benzoate
(continued on next page)
NEWBORN
& INFANT NURSING REVIEWS, MARCH 2009
41
Table 3 (continued)
Name
Method Squeaky Green Diaper
Cream, Rice Milk + Mallow
(Method Products, Inc.,
San Francisco, CA)
Lansinoh Diaper Rash Ointment
(Lansinoh Laboratories,
Alexandria, VA)
Sensi-Care Skin Protectant
(ConvaTec, Skillman, NJ)
Aloe Vesta Skin Protectant
(ConvaTec)
Carrington Moisture Barrier Cream
(Carrington Laboratories, Irving,
TX)
Ingredient List
Zinc Oxide (10%), Althaea officinalis extract, caprylic/capric triglycerides, cetyl
alcohol, cetyl hydroxyethylcellulose, decylene glycol, dimethicone, glycerin,
Helianthus annuus (sunflower) seed oil, Oryza sativa (Rice) bran extract, O sativa (Rice)
germ oil, phenoxyethanol, polysorbate 60, sorbitan stearate, water (agua), xanthan
gum
Dimethicone (5.5%) (skin protectant), USP modified lanonin (15.5%) (skin
protectant), zinc oxide (5.5%) (skin protectant), allantoin, beeswax, bisabolol,
caprylic/capric triglycerides, esters, glyceryl behenate/eicosadioate, Jojoba Chamomilla
recutita flower extract (Martricaria), petrolatum, polydecene, polyethylene,
propylparaben, stearyl glycyrrhetinate, tocopheryl acetate (vitamin E), Z mays (corn)
starch
Petrolatum (49%), zinc oxide (15%), carboxymethylcellulose sodium, water,
stearic acid, glycerin, cetyl dimethicone copolyol, polyglyceryl-4-isostearate, hexyl
laurate, phenoxyethanol
Petrolatum (43%), water, mineral oil, hydroxylated lanolin, sorbitan sesquioleate,
ozokerite, PEG-30 dipolyhydroxystearate, glycerin, steareth-20, magnesium sulfate,
DMDM hydantoin, iodopropynyl butylcarbamate, aloe barbadensis leaf juice
Petrolatum (90%), mineral oil and paraffin, acemannan hydrogel, butylparaben,
lecithin, propylparaben, purified water, quaternium 15, sodium chloride
The “skin protectant” is in bold. USP = United States Pharmacopea; BHA = butylated Hydroxy anisole; NF = normal form; PEG = polyethylene glycol.
Most contain zinc oxide, petrolatum, or mixtures and
compositionally appear to be similar. This is, perhaps, not
surprising given the number of ingredients that can be used to
make a “skin protectant claim.” Thicker products (pastes,
creams, ointments) usually have low water content. Pastes and
petrolatum barriers can be very occlusive. Some clinicians
recommend against their use for long periods and only in
situations where soils (feces) are high in water and
irritants.109,110 There are no studies on the use petrolatumbased barriers to prevent diaper dermatitis in normal diapered
skin.109 Products transfer onto the inner diaper sheet and may
interfere with absorbance of moisture from the skin.111
Some patients have conditions that affect fecal composition
(eg, gastrointestinal conditions) and may benefit from topical
agents designed to mitigate the specific irritants. For example,
cholestyramine binds with bile acids to make them inactive, and
Table 4. Ingredients in a Common Diaper Rash Cream and Their Functions
Ingredient
Zinc oxide (10%)
A barbadensis leaf juice
Cyclomethicone
Dimethicone
Fragrance
Methylparaben
Microcrystalline wax
Mineral oil
Propylparaben
Purified water
Sodium borate
Sorbitan sesquioleate
Vitamin E
White petrolatum
White wax
Function
Skin protectant claimed from monograph
Moisturizer, hydrating agent
Assists in spreading
Assists in spreading
Provides pleasant odor and/or covers ingredient odors
Preservative
Viscosity control
Emollient, solvent
Preservative
Solvent
Product pH control
Moisturizer, emollient
Vitamin at low level, effectiveness not established
Viscosity control
Viscosity control
Desitin Creamy ingredients: Zinc oxide (10%), A barbadensis leaf juice, cyclomethicone, dimethicone, fragrance, methylparaben, microcrystalline wax, mineral
oil, propylparaben, purified water, sodium borate, sorbitan sesquioleate, vitamin E, white petrolatum, and white wax.
42
VOLUME 9, NUMBER 1, www.nainr.com
Table 5. Surfactants Found in Skin Care
Products and the Relative Irritancy Potential
Relative Irritancy
High
Moderate
Low
Surfactants
Sodium lauryl sulfate
Sodium dodecyl sulfate
Sodium alkyl sulfate
Sodium or potassium cocoate
Sodium or potassium tallowate
Sodium palmitate
Sodium or potassium stearate
Linear alkyl benzene sulfate
Triethanolamine laurate
Sodium olefin sulfonate
Benzalkonium chloride
Dodecyl trimethyl ammonium
bromide
Sodium ethoxylates
Sodium laureth sulfate
Ammonium laureth sulfate
Sodium cocoyl isethionate
Sodium alkyl glycerol ether sulfonate
Sodium cocoyl sulfosuccinate
Disodium stearyl sulfosuccinate
preparations have been used successfully for severe perineal
skin breakdown.112-114 Cholestyramine ointments can be
prepared in hospital pharmacies. Sucralfate (Carafate; Marion
Merrell Dow, Kansis City, MO) in the form of an ointment or
powder has been used to treat skin damage from gastric
secretions. If candidiasis is also present, these patients must be
treated with an antifungal as well.115,116
Topical creams can be limited by poor substantivity and
removal by stool. Solutions and sprays that form a semipermeable barrier film upon drying are available. They are intended to
be left in place to protect the skin from direct irritant contact with
irritants. They are semipermeable to assist barrier repair. Skin
stripping during cleansing is minimized. Sureprep No-Sting
Protective Barrier Wipe (Sureprep NSPBW; Medline Industries,
Inc, Mundelein, IL) comes as a water-based solution, is
nonflammable, and has no age restrictions. Another is Cavilon
No-Sting Barrier Film (Cavilon NSBF; 3M Corporation, St Paul,
MN). The material is in volatile silicone solvent and dries to form
the semipermeable film. It can be used on infants older than 1
month (eg, not for use on preterms) and is flammable. Sureprep
NSPBW was evaluated in a small study in 10 NICU patients with
severe perineal skin breakdown.117 The skin condition, based on
assessment of area and severity, improved. Two were discharged
after 1 day. A trial of suitable size among parallel treatment
groups is necessary to determine the effectiveness of Sureprep
NSPBW vs other barrier creams, but it represents a potential
alternative for diaper skin breakdown in high-risk infants.
Skin cleansing Bathing practices vary with the infant's age and
medical condition. Skin cleansing products usually contain
NEWBORN
ingredients, surfactants (surface active agents), to emulsify soils
for removal during rinsing. Cleansers can be no-rinse liquids or
creams, in bar form, or liquids added to water. Because they
emulsify lipids, surfactants can damage the SC barrier and
cause skin irritation. Relative skin irritancy has been determined via skin testing, and rankings for common surfactants
are shown in Table 5. After cleaning, residual surfactant can
remain on the skin, especially when copious rinsing is not
practical.118 Liquid products containing surfactants with very
low irritancy are recommended for infants. The irritancy can
be determined by checking the ingredient label against the list
in Table 5.
Diaper skin can be cleansed with a soft cloth and an oilin-water lotion to assist in soil removal.119 Wipes composed
of a substrate with cleansing agents and/or emollients have
been developed for use on diaper skin. Wipe treatment
resulted in significantly lower erythema and surface roughness vs water plus an implement (cotton washcloth, cotton
wool balls) in healthy infants.120,121 Wipes made of a soft
nonwoven substrate containing water, nonionic cleansers,
and emollients resulted in reduced skin irritation (erythema,
rash) and TEWL vs cloth and water in critically ill premature and full-term neonates.122,123 Wipes used on diaper
skin should be free of alcohol, fragrance, and ingredients of
known irritancy or cytotoxicity and contain only essential
materials.109
Skin pH Reduction in diaper skin pH may be another strategy
for improving skin health. An acidic pH is important for the
enzymes involved in SC formation and integrity to be effective.
It contributes to the SC's innate immune function by
inhibiting colonization of pathogens, for example, Staphylococcus aureus.124-126 Application of a pH 5.5 buffer solution
increased the rate of barrier recovery after damage.127 Wipes
with pH buffers have been developed.128 Routine skin
cleansing with a new diaper wipe resulted in significantly
lower diaper skin pH than the hospital standard of cloth and
water in a trial among high-risk premature and full-term
infants.123 Provision of an acidic skin pH may also help reduce
the activity of fecal enzymes.
Other product ingredients and use on infants Published data
on the many products that touch, interact with, adhere to, or
influence the skin barrier of infants are very limited. Items
developed for the health and consumer skin care markets are
typically tested on adults and/or rely on marketplace experience
(lack of adverse effects) to support use on infants. They may
contain ingredients that should be avoided, if possible, or used
with caution.129 For example, products containing boric acid
are not recommended because of its toxicity.130,131 Benzalkonium chloride is used in skin products as a disinfectant or
preservative and should be evaluated before use on infants. It
has been implicated in allergic dermatitis in infants.132 The
ingredients are listed on the label and should be checked for
potential negative effects in the neonatal population before
being adopted for routine use.
& INFANT NURSING REVIEWS, MARCH 2009
43
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