Results

Recruitment

Recruitment to the trial took place between 19 November 2014 and 14 July 2016 and the last baby was randomised on 18 November 2016. During this time, 4963 families were assessed for eligibility, and of these 1484 families consented (30%) (Figure 6). The main reason families assessed for eligibility did not consent was due to declining (41% of those assessed). After the baby was born, 1395 babies were randomised (94%). Non-randomisation after consent was mainly as a result of no longer being eligible (n = 50), mostly as babies were born preterm (n = 41). One baby was randomly assigned in error 62 days after birth so was not included further. Of the 1394 babies, 693 were randomised to the emollient group and 701 to the control group (randomisation by site presented in Appendix 3, Table 28). The mean number of days between birth and randomisation was 5.8 [standard deviation (SD) 5.7]. Four babies were randomised more than 21 days after they were born.

FIGURE 6 Participant flow diagram to 24 months. a, Insufficient data collected to derive primary outcome for two participants (one in each group) at 24 months. (Figure not reproduced here; see the original article.)

Baseline characteristics

Family and baseline baby characteristics were well balanced across groups (Table 4). The mean age of the mothers at randomisation was 31 (SD 5.3), 32% of babies were delivered by caesarean section and 82% of babies had at least one first-degree relative with a history of eczema (parent report of doctor diagnosis).

Follow-up to 24 months

Follow-up of the infants between 3 and 24 months took place between February 2015 and November 2018. The questionnaires at 3, 6, 12 and 18 months were completed for around 75% at each time point and completion was similar in both groups (Table 5). No questionnaires were completed for 14% of participants in both groups (see Table 5).

At 24 months, follow-up was completed for 1212 randomised participants (87%, Figure 6) and completion was similar in both groups. Most visits (1123 in total) were completed face to face with a research nurse. For 89 participants, where a face-to-face visit was not possible, some data were collected via telephone, e-mail, SMS or post, although for two participants insufficient data were collected to be able to derive the primary outcome. Research nurses completing the skin examination reported becoming aware of which group the child was randomised to (or possibly becoming aware) for 30 participants in the intervention group and 11 participants in the control group. For 12 participants in the intervention group and 6 in the control group, the research nurses reported that this unblinding happened before the examination of the child’s skin. Families of infants where no primary outcome data were collected in both groups were more likely to have joined the study after the birth of their baby rather than consenting antenatally, had slightly younger mothers on average when they were born and were more likely to be in a household with other children (see Appendix 3, Table 31). A slightly greater proportion of girls had primary outcome data collected compared to boys in the intervention group with the opposite observed in the control group (see Appendix 3, Table 31). The number of family members with a history of atopic disease, delivery method and days between birth and randomisation were similar between infants with and without primary outcome data collected (see Appendix 3, Table 31).

Of the 1212 infants where the 24-month follow-up visit was completed, SPTs to assess allergic sensitisation were fully completed for 81% in both groups (Table 6). Five children were given antihistamines after the SPT. No children had a serious allergic reaction to the SPTs requiring the use of an auto adrenaline injector.

Based on the results of the SPTs and/or parent report of consumption and reaction to milk, egg and peanut, 258 children were invited to a food challenge for at least one of the three foods with similar numbers invited in the two groups (see Table 6). At least one food challenge took place for 69 children (27%). Similar numbers in each group had food challenges for peanut and cow’s milk. Twice as many children in the intervention group had a food challenge for egg compared to the control group (24 vs. 11). There were no incidents of the person completing the food challenge becoming unblinded to the group that the child was randomised to. The main reason that food challenges were not conducted was due to parents being unwilling to participate or due to the travelling distance to the two centres where the food challenges were conducted. For allergy to each food, more than 75% of diagnoses were made by panel consensus due to food challenges not being conducted. For some of these children, the panel made a diagnosis of possible food allergy or food allergy unlikely where there was insufficient information available to make a more definitive diagnosis; these diagnoses were included in a sensitivity analysis for the main food allergy outcome (see Table 6).

Adherence with the allocated intervention

For families in the intervention group, 509 (73%) responded to the telephone call at around 2 weeks to check whether they had received the skin-care pack and emollients, and to collect information on the date they started applying the emollient to the infant. Of those responding, the median age that families reported starting to apply the emollient was 11 days after birth [interquartile range (IQR) 7–17], and 452 (89%) reported starting to apply the emollient within 3 weeks of birth.

In the year after randomisation, around half of families in the intervention group reported usually applying the emollient every day (Table 7) and emollient was applied at least 3 days per week by 75%. Most families reported usually applying the emollient to the arms/legs and trunk and around three-quarters also reported usually applying it to the face/neck. Emollient was most commonly applied once a day and most families reported usually applying the emollient after bathing or showering their child. The small number of parents who said that they had not used the emollient at all at each time point reported several different reasons for this (see Table 7).

Of families with complete data on emollient use at each time point, 88% at 3 months, 82% at 6 months and 74% at 12 months reported using the emollient at least 3 days per week over the majority of the child’s body (compliance, Table 7). Complete data on adherence over the first year were collected for 442 infants (64%) and of these 311 (70%) infants were considered fully compliant with the intervention (as defined in Table 3). Using the conservative assumptions described in the Statistical methods section for participants with missing questionnaires, full compliance over the first year in the intervention group was estimated to be 51% (350/693) (see Appendix 3, Table 33).

In the control group, self-directed use of emollients at least 3 days per week to most of the body (contamination) was reported for 18% (82/457), 17% (62/372) and 15% (49/324) at 3, 6 and 12 months, respectively, for infants who did not have a parental report of a doctor diagnosis of eczema (see Appendix 3, Table 32).

Washing, feeding and other post-randomisation characteristics between birth and 24 months

Parent report of washing practices at 6, 12 and 24 months in terms of frequency, the products used to wash the child and use of oils in the child’s bath water were balanced across the two groups (see Appendix 3, Table 34). Between 12 and 24 months, just under half of the families in the intervention group and just under 30% in the control group reported using a moisturiser on their child at least 3 days per week to most of the body. This moisturiser use was more common in both groups in children with a parental report of a clinical diagnosis of eczema (see Appendix 3, Table 35).

At 6 months, parental report of the milk type used to feed their baby since birth and the introduction of solid foods was similar in the two groups (see Appendix 3, Table 36). Around 40% of babies in both groups had antibiotics in their first year and 50% in their second year of life (see Appendix 3, Table 36). Other characteristics such as additional children in the household, use of dust mite reduction measures, water softeners fitted in the house and whether the child regularly attended nursery or a playgroup were also similar in both groups (see Appendix 3, Table 36).

By 24 months, almost all children had eaten foods containing cow’s milk and egg and over three-quarters had eaten foods containing peanut (see Appendix 3, Table 37). The timing of the introduction of these foods was similar in the two groups. The percentage of children who had consumed these three foods recently and frequently at 24 months was also similar in the two groups (see Appendix 3, Table 37).

Primary outcome: diagnosis of eczema between 12 and 24 months of age

Primary analysis

A diagnosis of eczema between 12 and 24 months, defined as meeting the UKWP Criteria for Atopic Eczema, was present in 139 (23%) of 598 infants in the intervention group and in 150 (25%) of 612 in the control group. The adjusted RR of eczema in the intervention group compared to the control group was 0.95 (95% CI 0.78 to 1.16); p-value = 0.61 and adjusted risk difference –1.2% (95% CI –5.9% to 3.6%).

Sensitivity analysis

All sensitivity analyses conducted, including using multiple imputation for missing primary outcome data, were consistent with the primary analysis showing no difference between the two groups in the presence of eczema (Table 8).

Secondary analysis

The CACE estimate of the adjusted OR of eczema was 0.78 (95% CI 0.32 to 1.89; n = 1210) when compliance was defined as widespread emollient use over the child’s body at least 3 or more days per week over the first year of life (i.e. full compliance). The CACE estimate of the adjusted OR of eczema based in compliance in the first 3 months was 0.88 (95% CI 0.50 to 1.56; n = 1210).

Subgroup analysis

There was no evidence of an interaction effect with allocated group on the risk of eczema according to number of first-degree relatives with atopic disease, number of first-degree relatives with a history of eczema, FLG genotype, season of birth, water hardness or regular use of probiotics during pregnancy (see Figure 7, see also Appendix 3, Table 38).

FIGURE 7 Adjusted RR with 95% CIs in each subgroup for primary outcome of diagnosis of eczema between 12 and 24 months. (Figure not reproduced here; see the original article.)

Secondary outcomes

Eczema-related secondary outcomes

There were no differences between the groups in any of the secondary outcomes for eczema, including different definitions of eczema diagnosis (Table 9), time to onset of eczema (see Figure 8, Appendix 3, Figure 13 and Table 39) and severity of eczema (see Table 9, Figure 9 and Appendix 3, Table 40).

FIGURE 8 Time to onset of eczema based on first parental report of clinical diagnosis of eczema. (Figure not reproduced here; see the original article.)

FIGURE 9 Severity of eczema. (a) EASI at 24 months (blinded assessment of severity by research nurse) based on categories in Leshem et al.56 (b) POEM at 12 months (parent-reported severity) based on categories in Charman et al 2013. (c) POEM at 24 months. Reproduced from Chalmers et al.1 under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). (Figure not reproduced here; see the original article.)

Allergic rhinitis and wheezing at 24 months

The number and percentage of infants with parental-reported allergic rhinitis and wheezing between 12 and 24 months were similar in the two groups (Table 10).

Allergic sensitisation at 24 months

There was no evidence of a difference between the two groups in the percentage of infants with allergic sensitisation on SPT overall or to inhalant allergens, and although allergic sensitisation to milk, egg or peanut was more common in the intervention group, the CI for the difference between groups was wide and included the possibility of no effect (adjusted RR 1.36, 95% CI 0.94 to 1.95, Table 11).

Parental report of food allergy

For most measures of parental-reported food allergy in the first 2 years, including parental report of a clinical diagnosis of food allergy, there were slightly increased numbers in the intervention group compared with the control group. However, CIs were wide and included the possibility of no difference between the two groups (Table 12).

At 12 months, around 20% of parents in both groups reported that their child had had a reaction to at least one food since birth (see Table 12). At 24 months, just over 30% of parents reported that their child had had a reaction to at least one food since birth with more immediate reactions (within 2 hours of eating the food) in the intervention group compared to the control group (see Table 12). The number of children with a parental report of ever having any reaction to milk, egg or nuts and immediate reactions to milk, egg and peanuts were similar in the two groups at 24 months (see Table 12).

Confirmed diagnosis of food allergy

Seventy infants had a confirmed diagnosis of a food allergy to either milk, egg or peanut by either food challenge or panel consensus, which was the predefined main food allergy outcome. There were 41 participants with food allergy in the intervention group (7.5%) and 29 in the control group (5.1%) with adjusted RR of 1.47 (95% CI 0.93 to 2.33) (Table 13). A greater number of participants in the intervention group were confirmed allergic after a food challenge compared to the control group (15 vs. 6) due to more number of infants in the intervention group being confirmed allergic to egg at the food challenge (12 vs. 3) (see Appendix 3, Table 41). The number of infants diagnosed as allergic or possibly allergic by panel consensus was similar for each food (see Appendix 3, Table 41). Table 13 shows the between-group comparison of food allergy for milk, egg and peanut individually at 24 months as well as sensitivity analysis including infants with a panel consensus decision of food allergy possible or food allergy unlikely.

Results from sensitivity analyses using multiple imputation for missing outcomes of confirmed diagnosis of food allergy were consistent with the main analysis (see Appendix 3, Table 42). Subgroup analyses for FLG genotype and number of first-degree relatives with atopic disease or eczema found no evidence of an interaction (see Appendix 3, Table 43). The CACE could not be estimated when compliance was defined as widespread emollient use over the child’s body at least 3 or more days per week over the first year of life due to a problem with the estimation procedure (thought due to the small number with confirmed diagnosis of food allergy). The CACE estimate of the adjusted OR of confirmed food allergy based in compliance in the first 3 months was 1.79 (95% CI 0.62 to 5.14; n = 1115).

Safety outcomes

Infant skin infections between birth and 12 months were reported by a slightly greater number of parents in the intervention group than in the control group: 89 in the intervention group (15%) and 67 parents in the control group (11%) with an incidence rate ratio of 1.55 (95% CI 1.15 to 2.09; Table 14). The types of skin infections reported by parents were diverse with impetigo and unspecified bacterial, viral or fungal skin infections the most common if known (see Table 14).

The number of parents reporting infant slippage incidents within an hour of applying skin-care products to the baby’s skin was small (n = 26, < 3%) and similar in both groups (see Table 14). The trial management team rang parents of children reporting a slippage incident on the questionnaires to find out more about what happened. Of the 20 parents who responded, all confirmed with the trial team that the baby was okay, and that the slippage incident had not caused a serious injury.

Tables showing reported skin infections and slippages according to allocated group and reported emollient use are shown in Appendix 3, Table 44.

Tertiary outcomes

Follow-up for the tertiary outcomes

Follow-up for the tertiary outcomes at 36, 48 and 60 months took place between November 2017 and November 2021. Overall completion was 70% at each time point; however, completion was higher in the control group at all time points, particularly at 48 and 60 months (Table 15). At least one questionnaire was completed at 36, 48 or 60 months for 77% in the intervention group and 82% in the control group (see Table 15). Ninety-two per cent of participants had data for at least one follow-up time point between birth and 60 months (see Table 15).

The baseline characteristics of infants where the 60-month questionnaire was completed were similar in the two groups (see Appendix 3, Table 45). Families of infants in both groups where the 60-month questionnaire was not completed were more likely to have joined the study after the birth of their baby rather than consenting antenatally, had slightly younger mothers on average, were more likely to be of non-white ethnicity, were more likely to be in a household with other children, lived in areas on average with lower deciles of the Index of Multiple Deprivation and were less likely to have a first-degree relative with a history of eczema at randomisation (Appendix 3, Table 45). Follow-up completion at 60 months in both groups was slightly higher for participants who did not have eczema based on the primary outcome at 24 months compared to those with eczema (see Appendix 3, Table 46). Completion rates were similar according to other secondary outcomes at 24 months (see Appendix 3, Table 46).

Moisturiser use after 2 years

The percentage of parents reporting frequent moisturiser use (at least three times per week) over all or most of their child’s body in the previous year remained higher in the intervention group than the control group through to 60 months. In the intervention group, this frequent all-over moisturiser use in the past year was reported by 31% at 36 months (139/449), 25% at 48 months (114/459) and 22% at 60 months (99/448) compared to 20% at 36 months (94/471), 18% at 48 months (90/500) and 16% at 60 months (76/471) in the control group. In both groups and at all time points, this frequent whole-body moisturiser use was more common in children with a parental report of a clinical diagnosis of eczema (see Appendix 3, Table 35).

Eczema outcomes

Outcomes for eczema in the previous year at 36, 48 and 60 months were slightly higher in the intervention group than the control group; however, adjusted differences were small, and none were statistically significant. This was consistent across the tertiary outcomes for eczema based on parental report of a clinical diagnosis, parental completion of the UKWP Diagnostic Criteria for eczema (see Table 16) and parental opinion of whether their child had eczema (see Appendix 3, Table 48). There was also no difference between groups in the severity of eczema as measured by parent-reported symptoms on the POEM (see Table 16 and Appendix 3, Table 40).

Food allergy outcomes

Longer-term food allergy outcomes were also more common in the intervention than control group. Again, CIs were wide and the estimates for most outcomes were compatible with the role of chance. Parental reports of a reaction to any food within the previous year were significantly higher in the intervention group than the control group at both 36 and 48 months (Table 17). However, CIs for the difference between groups in parental report of immediate reactions to foods containing cow’s milk, egg or nuts and of a clinical diagnosis of food allergy in the previous year at 36 and 48 months were inconclusive (see Table 17). At 60 months, all outcomes relating to food allergy were similar between the two groups including parental report of an immediate reaction to any common food allergen (see Table 17). Full details of the foods that parents reported their child reacted are presented in Appendix 3, Table 49.

Wheezing and allergic rhinitis symptoms

At 36 months, fewer parents in the intervention group reported wheezing or whistling in their child’s chest in the previous year (adjusted RR 0.79, 95% CI 0.68 to 0.98; Table 18). The percentage of parents reporting that their child had been prescribed an inhaler for wheezing was also lower in the intervention group at 36 months (see Table 18). At 48 and 60 months, parental reporting wheezing or whistling in the previous year decreased in both groups with CIs including no difference between groups (see Table 18). The percentage of parents reporting that their child had been prescribed an inhaler for wheezing was also similar in the two groups at 48 and 60 months (see Table 18).

At 36, 48 and 60 months, the percentage of parents reporting that their child had had symptoms of allergic rhinitis in the previous year were similar in the two groups, with approximately a quarter of parents in each group reporting such symptoms at each time point (see Table 18).

Cumulative incidence outcomes

By 60 months, the percentage of parents who had reported that their child had had a clinical diagnosis of eczema or food allergy was similar in the two groups (Table 19). Thirty per cent of parents had reported a clinical diagnosis of eczema between 12 and 60 months and 15% of parents reported that their child had a clinical diagnosis of food allergy by 60 months.

Similarly, there was no difference between the two groups in the percentage of parents reporting that their child had had a clinical diagnosis of asthma or allergic rhinitis at 60 months (see Table 19).

Sensitivity analyses for parental report of a clinical diagnosis of eczema between 12 and 60 months and food allergy by 60 months exploring the impact of a worse outcome in those with missing data were consistent with the main analysis presented in Table 19 (see Appendix 3, Table 50).

There was no evidence of an interaction effect with allocated group on the risk of a parental report of eczema between 12 and 60 months according to FLG genotype (Table 20).

In exploratory tertiary outcomes for parental-reported reactions to egg or nuts by 60 months, 17% (101/597) of parents reported that their child had had a reaction in the intervention group compared to 13% (80/622) in the control group. The percentage of parents reporting that their child had had an immediate reaction to egg or nuts was similar in the two groups (12% intervention, 10% control, see Appendix 3, Table 51).