Objectives
Primary Objective
The primary objective of the study is to determine whether it is possible to establish effective behaviors for allergy prevention during early infancy in pregnant women who participate in an educational program developed by pediatric allergy specialists. Four months after birth, their behaviors will be compared against those of pregnant women who did not participate in the program.
Secondary Objectives
The secondary objectives are as follows:
・To determine whether the use of a moisturizer can reduce the onset of AD and eczema
・To determine whether the onset of other atopic disorders can be prevented by the use of a moisturizer.
・To examine the association between the onset of AD and food allergy sensitization.
・To establish the safety of the recommended moisturizer in neonates.
・To investigate the presence of allergies, skin condition, serum IgE, and TARC levels in neonates
Trial design
This study is an assessor-blinded, randomized, controlled, parallel-group comparison study (comparing our educational program group with an established childbirth education group) conducted in Chiba Aiyu-kai Kinen Hospital (hereafter referred to as “our hospital”) to examine the superiority of the educational program over established programs. Subjects are randomized in a 1:1 ratio into one of the two groups. The participants and study personnel are not blinded with respect to the assignments.
This protocol is written in accordance with the Standard Protocol Item: Recommendations for Interventional Trials (SPIRITS) guideline. Trial registration is through UMIN-CTR (R000038455).
Participants
Recruitment procedure
Participants are recruited among all pregnant women who visit our hospital for consultation regarding delivery. The investigator meets with each pregnant woman to provide oral and written information on the study and to request participation. Participants are selected according to the eligibility criteria. The pregnant women discuss participation with their respective families, and those who agree to participate in the study provide informed consent. After the collection of consent forms, the participants are randomized to one of two groups.
Eligibility criteria
Eligibility and exclusion criteria are as follows:
Eligibility criteria (individuals must meet two criteria):
- Those planning to give birth in our hospital
- Those planning to attend the childbirth education program provided by our hospital
Exclusion criteria (any of the following criteria):
- Those who were not planning to give birth in our hospital
- Those who did not attend our child birth education program
- Neonates younger than 36 weeks
- Low birth weight (<2000 g)
- Birth to triplets or more
- Children with serious congenital malformations
- Abnormal birth including fetal distress and neonatal asphyxia
- Other pregnant women and neonates assessed as inadequate for the study by a doctor
Intervention
Intervention arm
Pregnant women in the intervention arm participate in the childbirth education program established by the specialist and a pediatric allergy educator. The program was developed based on evidences supporting interventions on primary prevention, which are suggested to be beneficial to infant’s allergies in recent studies. In this program, we propose three types of barriers that protect infants from allergy: the intestinal mucosa, respiratory tract mucosa, and skin. We then recommend behaviors for mothers that improve the functions of these three types of barriers. Table 1 explains the details of the program using TIDieR47), a template for intervention description.
Control arm
A leaflet summarizing the content of the educational program that is provided to the intervention arm is made available to subjects in the control arm at approximately 20 and 30 weeks of pregnancy.
Measurements / Assessments
Primary outcomes
Self-evaluation of questionnaire to identify the behavioral characteristics of mothers based on the educational program at 4 months after delivery
Primary outcomes are evaluated according to a self-evaluation score at 4 months after delivery in both arms. The score is determined using a survey sheet created for this study (Appendix 1) to assess the behavioral characteristics of mothers. We prepared 21 questions to assess the dietary habits of mothers, living conditions, and the skin care of children based on the ideal behavior of mothers to prevent allergy in infants as proposed by specialists. Five options (a–e) are provided for all questions: a=1, b=2, c=3, d=4, and e=5. Higher scores indicate more appropriate behaviors of mothers to prevent pediatric allergy at each time point.
Secondary outcomes
We set the following seven secondary outcomes:
- Incidence and severity of atopic dermatitis and eczema infantile
The incidence and severity of AD and eczema in infants aged 1 week, 1 month, 4 months, and 12 months are determined by a blinded pediatrician according to the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2016 prepared by the Japanese Dermatological Association:
URL:https://www.dermatol.or.jp/uploads/uploads/files/guideline/atopicdermatitis_guideline.pdf
- Incidence of food allergy and sensitization to egg white, milk, and ovomucoid
The incidence of food allergy in infants aged 4 and 12 months is determined by sensitization using serum antigen-specific IgE 49), medical interview, and oral food challenge or a clear history of allergy triggered by accidentally ingested foods.
- Analysis of stratum corneum hydration, transepidermal water loss, and microscopic and digital images
Stratum corneum hydration in infants is measured 3–5 times on the left lower leg, forehead, and left cheek using Skicon-200EX® (IBS Japan Co., Ltd, Shizuoka, Japan). Transepidermal water loss (TEWL) is determined 2–3 times on the left lower leg, forehead, and left cheek using the VapoMeter® (DelfinTechnologies, Kuopio, Finland). Enlarged images of the skin of the left lower leg, forehead, and left cheek in infants are acquired using a USB microscope M3 (Scalar Corporation, Tokyo, Japan). Images of a wide range of skin surfaces in infants are obtained using a digital camera (Canon Tokyo, Japan). The skin is measured and photographed at 22°C and 50% humidity.
- TARC level
Serum TARC level is measured in infants aged 4 and 12 months to assess the severity of AD.
- Frequency of use and amount of moisturizer
The total amount of moisturizer used during the study is calculated to predict the effect of the educational program. The moisturizer is provided free of charge to those who want to use it.
- Questionnaire survey on living habits, awareness, and knowledge of mothers before and after pregnancy
A questionnaire survey on living habits, awareness, and knowledge of mothers before and after pregnancy was preparedbefore and after pregnancy, how they intend to provide nourishment for the baby, and their concerns regarding childcare and the skin care of the baby.
- Adverse events
Self-reported adverse events associated with the use of the moisturizer provided free of charge to those who want to use it during the study are recorded.
Baseline characteristics
The baseline characteristics are evaluated at approximately 20 weeks of pregnancy. The variables to be measured include age; delivery experience; history and type of allergy of the subject, their partner, and siblings; type of pet, if any; and smoking status of the subject and her family members living together.
Participant timeline
Table 2 shows the consent forms obtained from the subjects, intervention, and evaluation schedule.
Sample size
In this study, the number of deliveries per month at the investigational site was estimated at 15–20, and at most 120 participants are expected over the course of the 1-year study. A questionnaire aimed at identifying the behavioral characteristics of mothers was created for the study to assess primary outcomes. Currently, there are no data showing the effectiveness of the survey sheet. Considering the inclusion of 60 subjects per group with a significance level of 0.05 and a standard deviation of 16 under the conditions described above, the expected upper limit of the standard error of the mean was approximately 8 using a t-test with a statistical power of 80%. Based on this estimate, the final target sample size was set at 120 patients. The statistical power was calculated using R ver.3.5.2 statistical software (R Foundation for Statistical Computing, Vienna, Austria).
Randomization procedure and concealment of allocation
Participants who meet the eligibility criteria and agree to participate in the study are randomized after signing the informed consent form. These subjects are stratified according to the estimated delivery date into winter and other seasons, and randomized using the permuted block method. A statistical analyst generates a random allocation code using R statistical software (R Foundation for Statistical Computing) to randomize the subjects at each investigational site. The study is an assessor-blinded trial, and all raters are blinded with respect to the assignments. Also only the statistical analyst is aware of the stratification block size; the remaining staff is blinded. Subjects are randomized in a 1:1 ratio into one of two groups.
Statistical analysis
Full analysis set
Subjects enrolled in the study who started any of the study procedures are included in the full analysis set (FAS). However, those with a confirmed serious deviation from the protocol and those determined ineligible for the study after enrollment are excluded from the FAS.
Intention-to-treat analysis
In general, all statistical analyses are performed by the intention-to-treat principle.
Primary outcomes
Self-evaluation of questionnaire to identify the behavioral characteristics of mothers based on the educational program at 4 months after delivery
A linear mixed-effects model is used to analyze the total score of the questionnaire at 1, 4, and 12 months after delivery as an outcome variable. A mixed-effects model for repeated measurements (MMRM) 51),52) is used to properly handle missing values or dropouts that could arise during the study. An unstructured covariance structure is used to assess the correlation between outcomes at these time points. Mean changes from baseline t are modelled as outcome variables for the MMRM. Mean changes from baseline at each time point are analyzed individually using a regression model. If the regression parameters cannot be estimated using the unstructured model, the covariance structure is changed in the following sequence: Toeplitz matrix model, heterogeneous compound symmetry model, autoregressive model (1), compound symmetry model, and variance components model. A primary analysis is performed using estimates for the regression parameter or regression parameter test at 4 months after delivery. The significance level is set at 5% (two-sided).
Secondary outcomes
- Incidence and severity of atopic dermatitis and eczema infantile
The incidence of infantile AD and eczema infantile is compared between groups at all time points using Pearson's chi-squared test. The severity of these diseases is compared between groups using descriptive statistics of scores at each time point. Subgroup analyses are performed to assess the incidence and severity of AD related to the amount and frequency of moisturizer used during the study and the skin condition of infants.
2. Incidence of food allergy and sensitization to egg white, milk, and ovomucoid
The rate of sensitization to each allergen is compared between groups with a cut-off value of the incidence of food allergy and the serum antigen-specific IgE level (equal to or more than class II) in infants at each time point using Pearson's chi-squared test. Subgroup analysis is performed to assess the outcomes related to the amount and frequency of moisturizer used during the study and the onset of AD in infants.
- Analysis of stratum corneum hydration, transepidermal water loss, and microscopic and digital images
Descriptive statistics of the stratum corneum hydration, TEWL in infants s and rate of changes in the score at each time point are calculated and compared between groups. Subgroup analysis is performed to assess the amount and frequency of moisturizer used in infants during the study. In addition, an exploratory investigation is performed to evaluate the skin images.
4. TARC level
Descriptive statistics of the serum TARC level at each time point are calculated and compared between groups. Subgroup analysis is performed to assess the incidence of infantile AD and eczema infantile, and the amount and frequency of moisturizer used during the study.
5. Frequency of use and amount of moisturizer
Descriptive statistics of the total amount of moisturizer and rate of changes in the scores at each time point are calculated and compared between groups. An evaluation is performed considering birth month as a baseline characteristic.
- Questionnaire survey on living habits, awareness, and knowledge of mothers before and after pregnancy
Descriptive statistics of a questionnaire survey’s scores at each time point are calculated and compared between groups. Changes in the self-evaluation at each time point and the related factors are compared between groups.
Interim analysis
No interim analysis will be conducted.
Data collection procedure
All data will be analyzed by members specifically trained in the study protocol in our hospital.
Dissemination
Research ethics approval
The study will be performed according to the Declaration of Helsinki (adopted by the 18th World Medical Association General Assembly, 1964, including subsequent revisions) and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (Public Notice of the Ministry of Education, Culture, Sports, Science and Technology, and Ministry of Health, Labour and Welfare No. 3 of December, 2014). This study was approved by our hospital ethics committee.
Protocol amendments
Any amendments to the protocol will be submitted to the ethics committee of Chiba Aiyu-kai Kinen hospital for approval. Once approved, they will be reported to all the study investigators and, when necessary, to the study participants.
Confidentiality
All personnel involved in this study shall comply with the applicable laws and regulations regarding confidentiality. Study personnel must make every effort to protect confidential information on the subjects and must not disclose the information obtained during the study to any third party without due cause. This is binding for any personnel even after they are no longer directly associated with the study. The investigator, the person in charge of the study, and study collaborators shall use subject identification codes or registration numbers to enroll subjects and prepare case report forms instead of personal information that could be identified by a third party such as name, initials, address, telephone number, or medical chart number. With respect to information disclosure, the investigator or other personnel must carefully handle study data on the subjects to ensure that the data are not disclosed.
Research funding and conflicts of interest
The authors declare no conflicts of interest related to the plan, implementation, and reporting of the study results and interpretation of the results. Researchers independently planned and will conduct this study without funding or benefits from a company. Subjects do not lose any right or benefit by participating in this study.
Safety of subjects and compensation related to participation in the study
Subjects will need to allocate a certain amount of time to the study as follows: approximately 180 minutes for participation in sessions at 20 and 30 weeks of pregnancy, approximately 30 minutes for completing the questionnaire survey, and approximately 30 minutes for skin measurements at each time point. No special compensation is paid because adverse health effects are not expected, as the aim of the study is to educate subjects. However, if subjects experience any abnormal feelings during blood collection in the study, they must promptly contact the investigator to receive proper treatment.
Dissemination policy
The full protocol will be published in an academic journal in English. The study results will be announced to the public through presentations in academic meetings and publications in academic journals.