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\begin{document}

\title{Early initiation of short-term emollient use for the prevention of
atopic dermatitis in high risk infants -- the STOP AD randomised
controlled trial}



\author[1]{Jonathan Hourihane}%
\author[1]{Carol Ní Chaoimh}%
\author[1]{Dhanis Lad}%
\author[2]{Claudio Nico}%
\author[2]{Gerwin J. Puppels}%
\author[3]{X.F.Colin C. Wong}%
\author[3]{John E. Common}%
\author[1]{Deirdre Murray}%
\author[1]{Alan Irvine}%
\affil[1]{University College Cork}%
\affil[2]{A-D Druk BV}%
\affil[3]{Agency for Science Technology and Research}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background} Protecting the skin barrier in early infancy may
prevent atopic dermatitis (AD). We investigated if daily emollient use
from birth to 2 months reduced AD incidence in high risk infants at 12
months. \textbf{Methods} This was a single-center, two-armed,
investigator-blinded, randomized controlled clinical trial
(NCT03871998). Term infants identified as high risk for AD (parental
history of AD, asthma or allergic rhinitis) were recruited within 4 days
of birth and randomised 1:1 to either twice-daily emollient application
for the first 8 weeks of life (intervention group), using an emollient
specifically formulated for very dry, AD-prone skin, or to standard
routine skin care (control group). The primary outcome was cumulative AD
incidence at 12 months. AD \textless{}6 months was diagnosed based on
clinical presence of AD. The UK Working Party Diagnostic Criteria were
applied when diagnosing AD between 6 and 12 months. \textbf{Results} 321
infants were randomised (161 intervention and 160 control), with 61
withdrawals (41 intervention, 20 control). The cumulative incidence of
AD at 12 months was 32.8\% in the intervention group vs. 46.4\% in the
control group, p = 0.036 {[}Relative risk (95\%CI): 0.707 (0.516,
0.965){]}. One infant in the intervention group was withdrawn from the
study following development of a rash that had a potential relationship
with the emollient. There was no significant difference in the incidence
of skin infections between the intervention and control groups during
the intervention period (5.0\% vs. 5.7\%, P\textgreater{}0.05).
\textbf{Conclusions} This study has 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.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory
skin condition, characterized by dry, red and itchy
skin\textsuperscript{1,2}. AD usually begins in infancy and affects up
to one fifth of children \textsuperscript{3,4}. The pathogenesis
includes impaired skin barrier function as a significant pathomechanism,
along with cutaneous immune dysregulation and microbial
disturbances\textsuperscript{5}. Supporting this is the consistent
evidence that loss-of-function mutations in the filaggrin gene
(\emph{FLG} ), resulting in measurable skin barrier defects, plays a
central role in the inherited risk of AD \textsuperscript{6}.

Daily emollient use is a cornerstone of AD
management\textsuperscript{7}. Recently, the spotlight has been on the
potential role of emollients in infancy in preventing AD. Prompting this
were findings from two small randomised control trials (RCTs) reporting
that daily emollient application from birth until 6-8 months reduced AD
risk by up to 50\% \textsuperscript{8,9}. Unexpectedly, these findings
were not replicated in two much larger scale studies
\textsuperscript{10,11}. The Barrier Enhancement for Eczema Prevention
(BEEP) trial recruited 1394 high-risk infants and randomised them to
either daily emollient application for the first year or to standard
skin care advice alone\textsuperscript{10}. No evidence of a protective
effect of emollient use against AD at 1 or 2 years was found. The
Preventing Atopic Dermatitis and Allergies in Childhood (PreventADALL)
study involved baths for 5-10 minutes with added emulsified oil and
cream applied to the face after the bath on at least 4 days per week
from 2 weeks to 8 months and reported no effect on AD prevalence when
assessed 4 months later at 12 months. Another RCT where emollient was
applied daily to the face only from 0-6 months also reported no effect
\textsuperscript{12}. The data from these three RCTs largely contributed
to the conclusion of a recent meta-analysis that skin care interventions
probably do not influence AD development \textsuperscript{13}. This
meta-analysis used an individual participant data approach, excluding
studies only providing aggregate data. In contrast, another
meta-analysis including more studies found a beneficial effect of
emollients in high-risk infants {[}RR (95\% CI: 0.59 (0.43, 0.81){]},
but only when used up to the point of AD assessment and not when there
was an interval between the treatment and the assessment
\textsuperscript{14}.

The BEEP and PreventADALL studies used petroleum and paraffin-based
emollient formulations, \textsuperscript{10,11} and while Dissanayake et
al. used a more complex ceramide-based emollient, the latter study's
intervention involved application to the face only \textsuperscript{12}.
Data from a small pilot study suggest that emollients with ingredients
specifically designed to repair the skin barrier warrant further
investigation \textsuperscript{15}. Interventions in BEEP and
PreventADALL began at a median age of 11 days and from 2 weeks and
continued for 12 and 8 months, respectively \textsuperscript{10,11}.
Daily emollient application for an extended period in infancy places
considerable additional demands on new parents and may not be feasible
at a population level, especially if specialized and more expensive
emollients are advised. This may be reflected in the low adherence of
27\% to the intervention in PreventADALL \textsuperscript{11}. We have
shown that trans-epidermal water loss (TEWL) increased from birth to 2
months but stabilised thereafter \textsuperscript{16} suggesting a
shorter intervention period, beginning as soon as possible after birth
may represent a more feasible intervention, while targeting a critical
period of skin maturation.

This study aimed to investigate if daily emollient use from birth to 2
months can reduce the incidence of AD in high risk infants.

\textbf{Methodology}

\textbf{Study design}

Short-term Topical Application to Prevent Atopic Dermatitis (STOP AD)
was a single-centre, two-armed randomized control trial that postnatally
recruited newborn infants at high-risk of AD. Recruitment took place
between April 2019 and November 2020 in Cork University Maternity
Hospital (CUMH). Parents gave written informed consent prior to
participation. Term infants were identified as high-risk if they had at
least one parent with a history of AD, asthma or allergic rhinitis.
Exclusion criteria were: pre-term infant (born \textless{}37 weeks),
admission to the neonatal unit for issues other than feeding, receipt of
antibiotics in the maternity hospital, phototherapy, sibling already
recruited, other serious health conditions, severe widespread skin
condition or any condition that would make the emollient use inadvisable
or not possible (e.g. ankle talipes or hip dysplasia). The study was
conducted in accordance with the Helsinki Declaration and was approved
by the Clinical Research Ethics Committee of the Cork Teaching Hospitals
{[}ref ECM 5 (2) 18/12/18{]}.

\textbf{Randomisation}

Infants were randomised (1:1 allocation ratio) within 4 days of birth to
either twice-daily emollient application for the first 8 weeks of life
(intervention groupintervention - IG) or to standard routine skin care
advice (control group - CG). Parents and research nurses and staff
responsible for recruitment, taking measurements and administering
questionnaires were not blinded to study allocation. The study doctor
performing AD and food allergy assessments was not involved in
recruitment and was blinded throughout the study. Parents in the IG were
instructed to apply the emollient AVEENO\selectlanguage{ngerman}® Dermexa Fast \& Long Lasting
Balm (Johnson \& Johnson Santé Beauté France, JJSBF) twice-daily to the
whole body (excluding scalp) for the first 8 weeks. This product, with
oat ingredient, fatty acids and ceramides, developed specifically for
very dry itchy skin AD-prone skin, was supplied free to the study by the
manufacturer but is publicly available for sale and for use in this age
group. Emollient use after the intervention period was at parental
discretion. The CG were advised to follow the standard skin care advice
given at CUMH, which does not include regular emollient use, unless
indicated. Both groups were provided with AVEENO® Baby Daily Care Baby
Gentle Wash (JJSBF) to be used at their discretion. Adherence was
assessed using questionnaires at 2, 4 and 8-week and diaries completed
over the intervention period. Adherence to the intervention was defined
as using an emollient at least once daily. Contamination in the CG was
defined as emollient on four or more days per week.

\textbf{Study visits and procedures}

Study visits were at baseline (pre-discharge, within 4 days of birth)
and at approximately 2, 4 and 8 weeks and at 6 and 12 months. These
involved questionnaires on feeding, health, skin care and bathing;
repeat measurements of weight; TEWL and natural moisturising factor
(NMF) and monitoring of skin health.

\textbf{Skin barrier assessments}

TEWL was measured on the volar forearm using a closed chamber system
vapometer (Delfin Technologies, UK) after acclimatization to room
conditions for at least ten minutes.

\textbf{Filaggrin genotyping/stratification}

As a proxy for \emph{FLG} genotyping, NMF was measured \emph{in vivo} ,
non-invasively, at a depth of 25 \selectlanguage{greek}µ\selectlanguage{english}m in the stratum corneum of the thenar
eminence by Near-Infrared Raman spectroscopy (NMF-scan, RiverD
International B.V., Rotterdam, The Netherlands), a method that has
previously been shown to be an excellent proxy for \emph{FLG}
genotyping\textsuperscript{17--19}. Formal \emph{FLG} genetic testing as
performed as follows: buccal swabs were collected using Isohelix SK-3S
swabs and BFX/S1/05/50 buccal fix tubes (Cell Projects ltd). Filaggrin
genotyping was performed at the A*STAR Skin Research Labs using
Microfluidics PCR for full coverage of \emph{FLG} repeat alleles using a
method described previously\textsuperscript{20}.

\textbf{Atopic dermatitis assessment}

Parents were routinely encouraged to report skin concerns to the study
team. Suspected cases of AD were reviewed by the blinded investigator at
the earliest opportunity. Cases of AD \textless{}6 months were diagnosed
based on the presence of AD, assessed either in person or via
photographs when an in-person assessment was not possible. The UK
Working Party Diagnostic Criteria (UKWPDC) were applied when diagnosing
AD between 6 and 12 months \textsuperscript{21}. AD extent and severity
were evaluated (blinded) using SCORing Atopic Dermatitis (SCORAD) for
infants [?]6 months \textsuperscript{22}. During the high-level COVID-19
restrictions, AD assessments, including SCORADs, were completed remotely
by the blinded investigator using photographs and video links (see
supplementary data for impact of COVID-19 on study). AD cases were
treated with a standardized treatment program which included advice on
emollient use and a topical steroid treatment, where required.

\textbf{Food allergy assessment}

Parents were advised to introduce common food allergens including egg,
dairy and peanut early during weaning, as per national guidelines.
Suspected cases of food allergy were clinically assessed by the blinded
investigator and skin prick testing (SPT) was performed, as indicated.
Infants also had SPT to egg, dairy and peanut if they hadn't safely
consumed these foods by 12 months. Where deemed necessary by the allergy
team, those with a positive SPT or a reaction suggestive of food allergy
were invited for an oral food challenge (OFC).

\textbf{Outcomes}

The primary outcome was cumulative incidence of AD at 12 months.
Secondary outcomes included AD incidence at 6 months, cumulative
incidence of sensitization to food at 12 months and the evolution of
TEWL and NMF between 0-12 months.

\textbf{Sample size}

The target sample size was 242 (\emph{n} = 121 per group). This would
provide 80\% power at a 95\% confidence level to detect a 50\% reduction
in cumulative AD at 12 months from 30\% to 15\%. The expected AD rate of
30\% in this high risk group was based on data from a previous Irish
birth cohort study in the same geographical area \textsuperscript{23}.

\textbf{Data analysis}

Data were analysed based on a ``as randomized, complete-case'' approach,
where those missing an AD outcome were excluded. Groups were analysed
for the primary outcome as randomised, regardless of adherence to study
allocation. Sensitivity per-protocol analyses were conducted based on
adherence data from questionnaires and diaries. Using parent-reported
emollient data from questionnaires at 2, 4 and 8 weeks, participants in
the IG were included in the per-protocol analysis if they reported at
least once-daily emollient use at each of the three time-points. CG
participants were included if they reported emollient use of
\textless{}4 days per week at each time-point. In the diary per-protocol
analysis, participants in the IG were included if they recorded
emollient use on [?]90\% of days in the 8-week recording period, equating
to \textgreater{}6 days a week. CG participants were included if they
used emollient on [?]43\% of the days (\textless{}4 days a week).
Additional sensitivity analyses were conducted including those in the IG
who reported emollient use on [?]4 days a week and those who in the CG who
used emollient on\textless{}4 days3 days a week to more closely align
with the adherence definition used in the BEEP
study\textsuperscript{10}.

\textbf{Results}

\textbf{Recruitment/retention}

A total of 3059 infants were screened for eligibility between April 2019
and November 2020, of whom 321 were randomised (161 to intervention and
160 to control), Figure 1. Baseline characteristics were balanced across
the groups (Table 1). There were 61 withdrawals (41 intervention and 20
control, 19\% attrition), with the majority (80\%) occurring before the
2 week visit. The mean (SD) age at randomization was 1.9 (0.9) days.

\textbf{Protocol adherence}

In the questionnaires, most parents in the IG reported applying
emollient at least once daily in the first 8 weeks; 2 weeks: 89\%, 4
weeks: 91.7\%, 8 weeks: 86.6\% (Table 2). Twice-daily application was
reported by 63.3\% at 2 weeks, 69.2\% at 4 weeks and 73.1\% at 8 weeks.
Of those in the IG with questionnaires at all three time-points (n =
114), 89 (78.1\%) reported daily emollient use at all three time-points.
Less than 20\% of the CG reported emollient use on [?]4 days per week at
any of the time-points; 19\% at 2 weeks, 17.5\% at 4 weeks and 13.5\% at
8 weeks. Of those in the CG with questionnaires at all time-points (n =
132), 90 (68.2\%) reported using emollients on \textless{} 4 days per
week at all three time-points. There was no significant difference in
bathing frequency between the groups over the intervention period (See
supplementary data and Supplementary Table 7).

Diaries measuring adherence were returned by 95\% (114/120) of the IG
and 82.1\% (115/140) of the CG. The mean (SD) age that emollient use
started in the IG was 3.5 (1.5) days and 41.2\% (47/114) reported that
they applied emollient at least once on [?]90\% of recording days
(\textgreater{}6 days/week). A further 41.2\% (47/114) reported
emollient use for [?]75\% of recording days (\textgreater{}5 days/week).
Eighty percent (92/115) of the CG applied an emollient on [?]43\% of the
recording days ([?]3 days a week).

There was no significant difference in the prevalence of regular
emollient use ([?]4 days a week) between the groups at 6 and 12 months
(intervention vs. control: 29.6\% vs 29.7\%, p = 1.000 at 6 months and
28.4\% vs. 25.8\%, p = 0.868 at 12 months) (See Supplementary data and
Supplementary Table 8).

\textbf{Safety}

No family sought emergency medical assessment related to the study
intervention. Parent-reported skin infections during the 8-week
intervention period occurred in 5\% (6/120) of the IG and 5.7\% (8/140)
of the CG. One IG infant was advised to stop applying the emollient
after developing a rash that had a potential temporal relationship with
the emollient and was withdrawn from the study. Two suspected reactions
to the study emollient were investigated and confirmed as having no
relationship.

\textbf{Primary outcome}

The cumulative incidence of AD at 12 months was 32.8\% in the IG vs.
46.4\% in the CG, p = 0.036 {[}Relative risk (RR) (95\% CI): 0.707
(0.516, 0.965), Figure 2{]}. The point prevalence of AD at 12 months,
where the child met the UKWPDC at the assessment, was 20.5\% in the IG
vs. 38.2\% in the IG, p = 0.003 {[}RR (95\% CI): 0.536 (0.354,
0.813){]}.

\textbf{Secondary AD outcome}

The cumulative incidence of AD at 6 months was 18.3\% in the IG vs.
36.4\% in the CG, p = 0.002 {[}RR (95\%CI): 0.503 (0.325, 0,779){]}. The
point prevalence at 6 months was 18.3\% in the IG and 35.0\% in the CG,
p = 0.004 {[}RR (95\%CI): 0.524 (0.337, 0813){]}, Table 3.

Time-to-event survival analysis using the Kaplan- Meier method
demonstrates that the IG maintained AD-free skin for a longer period in
the first 12 months than the CG (p = 0.016, log-rank test, Figure 3). Of
those with AD outcome data at 6 and 12 months (\emph{n} = 117
intervention, \emph{n} =137 control), 7.7\% of IG and 8.0\% of CG
infants were diagnosed at [?]6 months, but no longer met the criteria at
12 months (p = 1.0). The prevalence of AD onset between 6 and 12 months
was 13.7\% and 9.5\% in the IG and CG, respectively (p = 0.397) and
10.3\% vs. 29.2\% met the criteria at both 6 and 12 months (p
\textless{} 0.001), (See Supplementary Figure 1). SCORADs were completed
for those [?]6 months at diagnosis (n = 55). There was no significant
difference in SCORAD total scores at diagnosis between the groups
{[}median (IQR) SCORAD: IG 11.3 (8.0, 18.4), vs. CG 12.3 (7.4, 16.0), p
= 0.888{]}.

A similar, but non-significant relative risk was observed for the
primary outcome in the per-protocol analyses {[}Questionnaire
per-protocol analysis RR (95\%) CI: 0.713 (0.501, 1.014), \emph{P} =
0.078); Diary per-protocol analysis RR (95\% CI): 0.745 (0.474,
1.173),\emph{P} = 0.253{]}, (See Supplementary Tables 1-4).

\textbf{Food allergen sensitization}

All infants had been introduced to dairy and almost all had been
introduced to egg (99.6\%) and peanut (98.0\%) by 12 months. Nine
infants had a positive SPT to at least one food {[}intervention; 3.3\%
(4/120), control; 3.6\% (5/120), p =1.0{]}.

\textbf{TEWL and NMF evolution}

There were no significant differences in TEWL or Thenar NMF between the
intervention and control groups at birth, 2, 4, 8 weeks or at 6 and 12
months (See Supplementary Tables 5 \& 6).

\textbf{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 \textless{}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 \textsuperscript{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 \textsuperscript{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 \textsuperscript{15,24}.
Following one of these \textsuperscript{15}, a larger scale RCT, the
PEBBLES study, involving twice-daily application of the same
ceramide-based emollient from 0-6 months is ongoing\textsuperscript{25}.
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)\textsuperscript{10}. Only 27\% of the IG fully adhered to the
protocol in PreventADALL which may have influenced the absence of a
protective effect \textsuperscript{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 \textsuperscript{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 \textsuperscript{15,24}. TEWL measurements are
influenced by environmental factors and more crucially for infants,
subject-specific parameters including stress and
crying\textsuperscript{26}. 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 (\textless{}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 \textsuperscript{23}. A possible explanation
for this is the \emph{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.



\textbf{References}

1. Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic
dermatitis. \emph{Nat Rev Dis Primer} . 2018;4(1):1.
doi:10.1038/s41572-018-0001-z

2. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. \emph{Lancet
Lond Engl} . 2020;396(10247):345-360. doi:10.1016/S0140-6736(20)31286-1

3. Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI. Global
variations in prevalence of eczema symptoms in children from ISAAC Phase
Three. \emph{J Allergy Clin Immunol} . 2009;124(6):1251-1258.e23.
doi:10.1016/j.jaci.2009.10.009

4. Nutten S. Atopic dermatitis: global epidemiology and risk
factors.\emph{Ann Nutr Metab} . 2015;66 Suppl 1:8-16.
doi:10.1159/000370220

5. Leung DYM. New insights into atopic dermatitis: role of skin barrier
and immune dysregulation. \emph{Allergol Int Off J Jpn Soc Allergol} .
2013;62(2):151-161. doi:10.2332/allergolint.13-RAI-0564

6. Drislane C, Irvine AD. The role of filaggrin in atopic dermatitis and
allergic disease. \emph{Ann Allergy Asthma Immunol Off Publ Am Coll
Allergy Asthma Immunol} . 2020;124(1):36-43.
doi:10.1016/j.anai.2019.10.008

7. McAleer MA, Flohr C, Irvine AD. Management of difficult and severe
eczema in childhood. \emph{BMJ} . 2012;345:e4770. doi:10.1136/bmj.e4770

8. Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of
the skin barrier from birth offers effective atopic dermatitis
prevention. \emph{J Allergy Clin Immunol} . 2014;134(4):818-823.
doi:10.1016/j.jaci.2014.08.005

9. Horimukai K, Morita K, Narita M, et al. Application of moisturizer to
neonates prevents development of atopic dermatitis. \emph{J Allergy Clin
Immunol} . 2014;134(4):824-830.e6. doi:10.1016/j.jaci.2014.07.060

10. Chalmers JR, Haines RH, Bradshaw LE, et al. Daily emollient during
infancy for prevention of eczema: the BEEP randomised controlled
trial.\emph{Lancet Lond Engl} . 2020;395(10228):962-972.
doi:10.1016/S0140-6736(19)32984-8

11. Skjerven HO, Rehbinder EM, Vettukattil R, et al. Skin emollient and
early complementary feeding to prevent infant atopic dermatitis
(PreventADALL): a factorial, multicentre, cluster-randomised
trial.\emph{Lancet Lond Engl} . 2020;395(10228):951-961.
doi:10.1016/S0140-6736(19)32983-6

12. Dissanayake E, Tani Y, Nagai K, et al. Skin Care and Synbiotics for
Prevention of Atopic Dermatitis or Food Allergy in Newborn Infants: A 2
\selectlanguage{ngerman}× 2 Factorial, Randomized, Non-Treatment Controlled Trial. \emph{Int
Arch Allergy Immunol} . 2019;180(3):202-211. doi:10.1159/000501636

13. Kelleher MM, Cro S, Van Vogt E, et al. Skincare interventions in
infants for preventing eczema and food allergy: A cochrane systematic
review and individual participant data meta-analysis. \emph{Clin Exp
Allergy J Br Soc Allergy Clin Immunol} . 2021;51(3):402-418.
doi:10.1111/cea.13847

14. Zhong Y, Samuel M, van Bever H, Tham EH. Emollients in infancy to
prevent atopic dermatitis: A systematic review and
meta-analysis.\emph{Allergy} . Published online September 30, 2021.
doi:10.1111/all.15116

15. Lowe AJ, Su JC, Allen KJ, et al. A randomized trial of a barrier
lipid replacement strategy for the prevention of atopic dermatitis and
allergic sensitization: the PEBBLES pilot study. \emph{Br J Dermatol} .
2018;178(1):e19-e21. doi:10.1111/bjd.15747

16. Kelleher M, Dunn AG, Irvine A, Smith H, Hourihane OJ. O08 -
Increased early life Transepidermal Water Loss (TEWL) values can predate
atopic dermatitis in asymptomatic infants: results from the BASELINE
study. \emph{Clin Transl Allergy} . 2014;4(1):O8.
doi:10.1186/2045-7022-4-S1-O8

17. Caspers PJ, Lucassen GW, Carter EA, Bruining HA, Puppels GJ. In vivo
confocal Raman microspectroscopy of the skin: noninvasive determination
of molecular concentration profiles. \emph{J Invest Dermatol} .
2001;116(3):434-442. doi:10.1046/j.1523-1747.2001.01258.x

18. Ní Chaoimh C, Nico C, Puppels GJ, et al. In~vivo Raman spectroscopy
discriminates between FLG loss-of-function carriers vs wild-type in day
1-4 neonates. \emph{Ann Allergy Asthma Immunol Off Publ Am Coll Allergy
Asthma Immunol} . 2020;124(5):500-504. doi:10.1016/j.anai.2020.01.022

19. O'Regan GM, Kemperman PMJH, Sandilands A, et al. Raman profiles of
the stratum corneum define 3 filaggrin genotype-determined atopic
dermatitis endophenotypes. \emph{J Allergy Clin Immunol} .
2010;126(3):574-580.e1. doi:10.1016/j.jaci.2010.04.038

20. Wong XFCC, Denil SLIJ, Foo JN, et al. Array-based sequencing of
filaggrin gene for comprehensive detection of disease-associated
variants. \emph{J Allergy Clin Immunol} . 2018;141(2):814-816.
doi:10.1016/j.jaci.2017.10.001

21. Williams HC, Burney PG, Pembroke AC, Hay RJ. The U.K. Working
Party's Diagnostic Criteria for Atopic Dermatitis. III. Independent
hospital validation. \emph{Br J Dermatol} . 1994;131(3):406-416.
doi:10.1111/j.1365-2133.1994.tb08532.x

22. Kunz B, Oranje AP, Labrèze L, Stalder JF, Ring J, Taïeb A. Clinical
validation and guidelines for the SCORAD index: consensus report of the
European Task Force on Atopic Dermatitis. \emph{Dermatol Basel Switz} .
1997;195(1):10-19. doi:10.1159/000245677

23. O'Donovan SM, Murray DM, Hourihane JO, Kenny LC, Irvine AD, Kiely M.
Cohort profile: The Cork BASELINE Birth Cohort Study: Babies after
SCOPE: Evaluating the Longitudinal Impact on Neurological and
Nutritional Endpoints. \emph{Int J Epidemiol} . 2015;44(3):764-775.
doi:10.1093/ije/dyu157

24. McClanahan D, Wong A, Kezic S, et al. A randomized controlled trial
of an emollient with ceramide and filaggrin-associated amino acids for
the primary prevention of atopic dermatitis in high-risk infants.\emph{J
Eur Acad Dermatol Venereol JEADV} . 2019;33(11):2087-2094.
doi:10.1111/jdv.15786

25. Lowe A, Su J, Tang M, et al. PEBBLES study protocol: a randomised
controlled trial to prevent atopic dermatitis, food allergy and
sensitisation in infants with a family history of allergic disease using
a skin barrier improvement strategy. \emph{BMJ Open} .
2019;9(3):e024594. doi:10.1136/bmjopen-2018-024594

26. Stamatas GN, Nikolovski J, Mack MC, Kollias N. Infant skin
physiology and development during the first years of life: a review of
recent findings based on in vivo studies. \emph{Int J Cosmet Sci} .
2011;33(1):17-24. doi:10.1111/j.1468-2494.2010.00611.x

\textbf{Table 1} Baseline characteristics\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Intervention (n = 161)\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Control (n = 160)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Maternal characteristics}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Age {[}mean (SD) years{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
33.3 (4.4)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
34.1 (4.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Country of birth (Ireland)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
142 (88.2)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
139 (86.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Ethnicity (white)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
156 (96.9)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
158 (98.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Paternal characteristics}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Age {[}mean (SD) years{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
35.3 (5.7)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
35.9 (5.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Country of birth (Ireland)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
142 (88.2)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
143 (89.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Ethnicity (white)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
157 (97.5)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
159 (99.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Infant characteristics}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Sex (male)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
79 (49.1)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
85 (53.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Gestational age {[}mean (SD) weeks{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
39.7 (1.1)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
39.5 (1.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Birth weight {[}mean (SD) kg{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
3.6 (0.4)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
3.6 (0.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Mode of delivery\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Vaginal\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
98 (61.3)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
103 (64.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Caesarean section\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
62 (38.8)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
57 (35.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Age randomised {[}mean (SD) days{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.9 (1.0)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.8 (0.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Baseline TEWL {[}median (IQR) gwater/m2/h{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
9.31 (7.25, 12.41)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
9.25 (7.44, 13.31)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Baseline NMF {[}median (IQR) g/g protein{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.32 (0.22, 0.42)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.33 (0.25, 0.41)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Family history of atopy}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Maternal atopy\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Allergic rhinitis\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
81 (50.3)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
63 (39.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Atopic dermatitis\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
40 (24.8)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
56 (35.0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
54 (33.5)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
63 (39.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Any maternal atopy\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
112 (69.6)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
107 (67.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Paternal allergy\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Allergic rhinitis\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
66 (41.8)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
75 (47.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Atopic dermatitis\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
43 (27.2)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
45 (28.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
56 (35.4)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
53 (33.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Any paternal atopy\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
101 (63.9)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
107 (67.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Two parents with atopic history\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
52 (32.9)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
54 (34.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Participant with at least one sibling\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
87 (54.0)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
94 (58.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\emph{Of which, at least one sibling with}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Allergic rhinitis\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
20 (23.0)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
21 (22.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Atopic dermatitis\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
35 (40.2)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
41 (43.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
12 (13.8)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
13 (13.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\emph{FLG} genotyping\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{FLG} wildtype\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
96/117 (82.1)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
113/136 (83.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{FLG} null mutation (one)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
21/117 (17.9)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
22/136 (16.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{FLG} null mutation (two)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
1/136 (0.7)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Data are n (\%) unless stated otherwise.

Abbreviations : TEWL = Transepidermal water loss, NMF = Natural
mositurising factor, \emph{FLG} = gene encoding filaggrin

\textbf{Table 2} Parent-reported emollient application frequency at 2, 4
and 8 weeks (questionnaire data)\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Intervention (\emph{n} = 120)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Intervention (\emph{n} = 120)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Intervention (\emph{n} = 120)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Control (\emph{n} = 140)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Control (\emph{n} = 140)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Control (\emph{n} = 140)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{2 weeks} \textbf{(\emph{n} = 118)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{4 weeks (\emph{n} = 120)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{8 weeks (\emph{n} = 119)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{2 weeks} \textbf{(\emph{n} = 137)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{4 weeks} \textbf{(\emph{n} = 137)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{8 weeks} \textbf{(\emph{n} = 140)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Never\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
47 (34.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
39 (28.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
34 (24.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Occasionally\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1 (0.8)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
25 (18.2)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
25 (18.2)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
25 (17.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Once/week\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1 (0.8)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2 (1.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
7 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
9 (6.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10 (13.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2-3/week\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3 (2.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3 (2.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5 (4.2)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
32 (23.4)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
40 (29.2)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
44 (31.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4-6/week\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
8 (6.8)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6 (5.0)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
9 (7.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
16 (11.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
17 (12.4)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11 (7.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Daily\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
105 (89.0)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
111 (91.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
103 (86.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10 (7.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
7 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
8 (5.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Twice/day\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
75 (63.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
83 (69.2)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
87 (73.1)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2 (1.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Data are n (\%)

\textbf{Table 3} Atopic dermatitis outcomes at 6 and 12 months\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Total\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Intervention\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Control\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
P-value\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Relative Risk (95\% CI)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Primary outcome\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cumulative AD at 12 months\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
103/257 (40.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
39/119 (32.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
64/138 (46.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.036\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.707 (0.516, 0.967)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Secondary outcomes\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
AD at 12 months\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
AD according to the UK Working Party Diagnostic
Criteria\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
76/253 (30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
24/117 (20.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
52/136 (38.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.003\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.536 (0.354, 0.813)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
AD at 6 months\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
AD according to the UK Working Party Diagnostic
Criteria\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
71/260 (27.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
22/120 (18.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
49/140 (35.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.004\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.524 (0.337, 0.813)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cumulative AD\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
73/260 (28.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
22/120 (18.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
51/140 (36.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.002\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.503 (0.325, 0.779)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{+} Point prevealance.

Abbreviations: AD = atopic dermatitis

\textbf{Figures}

\textbf{Figure 1} Trial profile

\textbf{Figure 1 legend:} *Two infants in the control group were no
longer eligible due to receiving phototherapy for jaundice after
randomization. The primary outcome was the cumulative incidence of
atopic dermatitis at 12 months.

Abbreviations: CW = Consent withdrawn, LTFU = Lost to follow-up

\textbf{Figure 2} Point prevalence and cumulative incidence of AD at 12
months in the intervention and control groups

\textbf{Figure 2 legend:} The point prevalence of AD was calculated
based on the number of infants in each group who met the UK Working
Party Diagnostic Criteria for atopic dermatitis at 12 months
(intervention: 24/117, control: 52/136), as assessed by the blinded
investigator. The cumulative incidence of AD was calculated based on the
number of infants diagnosed with AD at any point in the first 12 months
(intervention: 24/117, control: 52/136).

Abbreviations: AD = atopic dermatitis

\textbf{Figure 3} Kaplan-Meier plot of the proportion of in infants in
the intervention and control group

without AD during the first 12 months of life

\textbf{Figure 3 legend:} The intervention group maintained AD-free skin
for a longer period in the first 12 months than the control group
(\emph{P} = 0.016, log-rank test).

Abbreviations: AD = atopic dermatitis\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-N--Chaoimh-ALL-06/Figure-2-N--Chaoimh-ALL-06}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-N--Chaoimh-ALL-06/Figure-1-N--Chaoimh-ALL-06}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-N--Chaoimh-ALL-06/Figure-3-N--Chaoimh-ALL-06}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

