Discussion
In this RCT in high-risk infants, we found that daily emollient use
initiated in the first week of life until 2 months is associated with a
significant reduction in the cumulative incidence of AD at 12 months.
Daily emollient use was associated with a 50% and 29% reduction in the
risk of the cumulative incidence of AD at 6 and 12 months, respectively.
Similar risk reductions were observed in the per-protocol analyses where
only those in the intervention and control groups were included if they
used emollients at least once daily and <4 days a week,
respectively. However, these were not significant for the primary
outcome which may be due to the conservative adherence criteria applied
and thus, lower numbers included in the analysis and therefore lower
power to detect differences between the groups.
While some AD cases diagnosed before 6 months had resolved by 12 months,
there was no difference in transient cases between the groups. As we did
not collect longer term data, we cannot exclude the possibility that the
intervention may have only delayed the onset of AD beyond 12 months. A
recent meta-analysis reported a protective effect of emollients but only
when there was no interval between the emollient treatment and AD
assessment 14. However, there was significant
heterogeneity between the four studies included in that analysis. In our
study, a 29% reduction in the risk of cumulative AD at 12 months, was
maintained 10 months after the intervention.
Our findings are at variance with recent findings from two large RCTs,
where no evidence of a protective effect of emollient use in the first
year against AD was found 10,11. Among the most
notable differences between these RCTs and ours was the timing of the
intervention. The treatment in STOP AD began within days of birth during
a dynamic period of skin maturation and adaption to the dramatic
environmental changes of life ex utero. In STOP AD, infants were
randomised within 4 days of birth with the IG advised to begin the
emollient treatment immediately. In BEEP, the median (IQR) age that
emollient use began was 11 days (7, 17) days, with only 89% starting
emollient application before 3 weeks. In PreventADALL, the intervention
began from 2 weeks of age.
The emollients used in BEEP and PreventADALL were basic petroleum and
paraffin-based formulations, respectively. The emollient used in this
study consists of a formulation with added ceramides developed
specifically for very dry itchy skin. Two small studies that also used
more complex ceramide-rich emollients reported non-significant trends
towards a protective effect against AD 15,24.
Following one of these 15, a larger scale RCT, the
PEBBLES study, involving twice-daily application of the same
ceramide-based emollient from 0-6 months is ongoing25. Here we showed a reduced risk of AD at 12 months
with a short 2-month intervention period, which may represent a more
feasible and family friendly strategy for AD prevention.
Our high adherence rates demonstrate the feasibility of implementing a
regimen of daily emollient use during the first 2 months of life.
Adherence rates using the diaries were lower than reported on the
questionnaires but 82.4% still reported using emollients on ≥75% of
days equating to over 5 days a week. While infants in this study were
followed closely during the intervention period, similar rates of
adherence were observed in BEEP which involved limited contact, but used
a less strict definition for adherence (emollient use ≥3 days/week)10. Only 27% of the IG fully adhered to the protocol
in PreventADALL which may have influenced the absence of a protective
effect 11.
While we did assess food allergy outcomes, this study was not powered to
detect a reduction in food allergy risk. Unlike BEEP, where a
non-significant increase in food allergy in the IG has been prominently
reported (15), we found no difference in the prevalence of food allergy
between the groups. While we did not use SPTs to screen for food
allergy, almost all infants had tried the most common food allergens -
milk, egg and peanut - by 12 months, so the rate of food sensitization
and allergy reported is likely reflective of the true rate in our
groups. BEEP reported a higher rate of skin infections in the IG, with
suggestions of the possibility of greater pathogen exposure with
emollient application 10. We did not find evidence of
an increased risk of skin infections with short-term emollient use.
Despite the reduction of AD risk in the IG, there was no difference in
TEWL throughout the first year between the groups. Other studies on
emollient use during infancy reported a similar absence of an effect of
the intervention on TEWL 15,24. TEWL measurements are
influenced by environmental factors and more crucially for infants,
subject-specific parameters including stress and crying26. This may have affected our ability to detect
differences between the groups.
The major strength of this study is the initiation of emollient use
within days of birth in the IG. Other strengths include the close
follow-up of infants, a high rate of adherence in the IG and a low rate
of contamination in the CG.
A limitation to this study is that in response to the COVID-19 pandemic,
many AD diagnoses were made remotely. To mitigate this, detailed
information and photographs were collected when making a diagnosis.
SCORAD assessments were also completed remotely, which may have affected
assessments of AD severity. Validated diagnostic criteria could not be
applied when diagnosing earlier onset AD (<6 months), where
cases were diagnosed based on presence of AD lesions. However, of the 73
infants diagnosed with AD ≤6 months, 71 (97.3%) met the UKWPDC at 6
months. The prevalence of cumulative AD in this group was higher than
expected based on the rates among infants with parental history of atopy
in an Irish birth cohort 23. A possible explanation
for this is the a priori recruitment of high-risk infants and the
close monitoring of skin health in this study. Only a third (32.1%) of
those eligible for this study were recruited. One of the main reasons
for the refusal to participate was the demanding follow-up schedule
involved, particularly during the intervention period that started
before going home with their newborn baby, suggesting that more
motivated individuals were recruited. We also had a higher rate of
withdrawals in the first two weeks of life, particularly in the
intervention group, mainly due to withdrawal of consent and not due to
early onset of AD by this time. This is a consideration in assessing the
feasibility of advising daily emollient use in the early postnatal
period to a more general population.
We have demonstrated that early initiation of daily specialized
emollient use until 2 months reduces the incidence of AD in the first
year of life in high-risk infants. The mechanisms behind this are
unclear but analysis of microbiome diversity and inflammatory biomarkers
in a subgroup of this study is ongoing and may provide further
information. While several recent studies do not support a protective
effect of emollient use in infancy, future studies should examine the
use of more complex emollients directed at enhancing the skin barrier,
while identifying a treatment window that is both effective and
acceptable to parents.