Perinatal Environmental Health Education Intervention to Reduce Exposure to Endocrine Disruptors: The PREVED Project

Environmental health promotion interventions may reduce endocrine disruptor (ED) exposure. The PREVED (PREgnancy, preVention, Endocrine Disruptors) project was developed to improve knowledge, to enhance risk perception, and to change exposure behavior. Our objective was to present the phases of the PREVED project using the RE-AIM method. PREVED intervention consisted of three workshops during pregnancy. Reach, adoption, and implementation phases were assessed with qualitative studies. Efficacy study consisted of a three-arm randomized controlled trial (RCT) on 268 pregnant women: (i) control group (leaflet), (ii) intervention group in neutral location, (iii) intervention group in contextualized location. The main outcome was the percentage evolution of participants who reported consuming canned food. Secondary outcomes were evolution of psycho-social scores, evolution of ED presence in urine, and ED presence in colostrum. The intervention adoption was centered on upper-privileged women, but implementation assessment showed that key features (highly practical intervention) seemed to be carried out and had initiated some behavior changes. A total of 268 pregnant women participated in the intervention and 230 in a randomized controlled trial (control group: 86 and intervention groups: 172). We found no significant differences in consumption of canned food and in percentage of women having a decrease of bisphenol A or parabens in urine, but we found a significant increase in the evolution of risk perception score and overall psychosocial score in intervention groups (respectively: +15.73 control versus +21.03 intervention, p = 0.003 and +12.39 versus +16.20, p = 0.02). We found a significant difference in percentage of women with butylparaben detection between control group and intervention groups (13% versus 3%, p = 0.03). PREVED intervention is the first intervention research dedicated to perinatal environmental health education in France. By sharing know-how/experience in a positive non-alarmist approach, it improved risk perception, which is key to behavior change, aiming to reduce perinatal ED exposure. Including women in precarious situations remains a major issue.


Background
Endocrine disruptors (EDs) are present everywhere in our daily life. Defined by the World Health Organization (WHO) as "exogenous substance or mixture that alters (7 neutral and 4 contextualized), interviews with 3 facilitators and 4 pregnant women, and satisfaction assessment of 18 workshops representing the views of 111 participants. This study analyzed the key features of program delivery as adaptations during workshops to meet specific needs of participants, behavioral techniques to engage them and remove barriers. It clarified the way the program sought to make pregnant women change their lifestyle choices and how they perceived workshops.
Maintenance was defined as the extent to which programs had potential for sustainability. It was measured by the number of workshops done after the end of the study, the number of sites continuing to deliver the program and the efficacy outcomes evolution.
Effectiveness was measured by merging efficacy and implementation evaluations.

Efficacy Assessment Efficacy Study Design
To assess efficacy, an open-label monocentric, randomized controlled trial (RCT), parallel-designed was conducted. Eligible women were identified from the list of pregnancy declarations centralized by "Protection Maternelle et Infantile" or PMI (maternal and child protection). The modalities of recruitment were detailed in the protocol article [16]. Central random blind-generated allocation with 1:1:1 ratio was performed based on fixed blocks of three before t0. The allocation sequence was generated on Microsoft EXCEL ® (function RAND). Pregnant women were randomly assigned to one of the three groups in the 1st trimester of pregnancy: (i) Control group (leaflet on EDs); (ii) Intervention group in neutral location (leaflet on EDs and collective workshops in a meeting room); (iii) Intervention group in contextualized location (leaflet on EDs and collective workshops in the real-life pedagogical apartment).
Three workshops were conducted during the 2nd and 3rd trimester of pregnancy, they focused on three themes: (i) indoor air quality (animated by a medical advisor for indoor environments), (ii) nutrition (animated by dietician trained in environmental health), and (iii) personal care products (animated by a cosmetologist).

Efficacy Study Outcomes
The main outcome was percentage evolution of participants who reported consuming canned food before and after intervention. This percentage was determined through a consumption questionnaire (Q1) developed by our research team [3] and administered at t0, t + 2 months, and t + 14 months. Q1 explored the various food consumption that could be a source of exposure to EDs.
Secondary outcomes were mean score evolution of psychosocial dimensions such as risk perception, self-esteem, sense of coherence, locus of control. These scores were determined through a psychosocial questionnaire (Q2) also developed by our research team: the PREVED© questionnaire [15], and administered at t0, t + 2 months, and t + 14 months. Q2 was structured on the basis of the Health Belief Model (HBM) [20] and explores: (i) ED knowledge; (ii) Risk from EDs; (iii) Risk Assessment of EDs; (iv) Perceived Ability to avoid ED exposure. The efficacy of the program was therefore assessed in terms of the knowledge, attitudes, and practices (KAP) of participants towards ED exposure.
BPA and ClxBPA in urine samples were assayed by Ultra High-Performance Liquid Chromatography coupled with tandem Mass Spectrometry (LC-MS/MS) according to the method developed and validated by our team [21]. The description of sampling, transport, and storage of samples before analysis is detailed in the protocol article [16] (Supplementary  Table S1).
To compare groups, a first variable defined whether each sample was below the LoD (Limit of Detection), above the LoQ (Limit of Quantification), or between these two thresholds. A second dynamic variable between two urinary stages defined three categories of development: decreasing variable (e.g., drop from superior to LoQ to below LoD), stability of the variable or rising variable (e.g., from below LoD to an intermediate level between LoD and LoQ). Whenever possible, for left-censored data less than 80%, data imputation by minimum of LoQ divided by two (LoQ/2 for samples below the LoQ) and by Truncation k-Nearest Neighbor imputation (kNN-TN) was performed [22], enabling quantitative analysis.

Statistical Analysis
Intervention exposure was defined as "having participated in at least two workshops". Sensibility analysis was defined being exposed, if having participated in at least one workshop.
A descriptive analysis was performed on sociodemographic data, questionnaire scores, and on presence or concentrations of EDs, with mean and standard deviation for quantitative variables, and percentage for qualitative variables; paired t-tests were used to compare mean differences and χ 2 -test was used to compare percentages.
The Q1 mainly quantifies the number of (a) canned tuna/week; (b) preserved sweetcorn/week; (c) other canned food/week; (d) total canned food consumption/week; (e) canned drinks/day; (f) plastic drink bottles/week. We compared the evolution from before to after intervention of these consumptions between control group (Group 1) and intervention groups (Group 2 + 3).
The Q2 mainly quantifies an overall psychosocial score summing four sub-scores: ED knowledge; Perceived Ability to avoid ED exposure; Risk from EDs (perceived severity score); Risk Assessment of EDs (perceived vulnerability score). A risk perception score was calculated based on perceived severity and vulnerability [15].
Main ED presence or concentration statistics were performed between control group (Group 1) and intervention groups (Group 2 + 3). Additional analysis was performed for sub-group analysis (Group 2 versus Group 3).
We performed statistical modelling with risk perception as dependent variable and EDs risk perception determinants [23], such as socio-economic status and age, as independent variables, with linear multiple regression. We performed the same statistical modelling with overall psychosocial score.
Per-protocol (PP) analysis was performed to assess the effect of workshops on consumption, psychosocial variables, and ED presence or concentrations. Depending on the conditions of use, χ 2 or Fisher tests were carried out for percentage comparison. After imputation of ED concentration, Student or Wilcoxon tests were carried out for mean comparison. We used ANOVA (analysis of variance) to compare means of the groups.  In fine, 135 (60 in neutral location, 75 in contextualized location) of pregnant women followed the workshop among 4393 eligible women who received informative postal mail with a prepaid envelope.

Qualitative Analysis
Our ultimate purpose being to reach all pregnant women including disadvantaged populations, we chose an underprivileged and multicultural neighborhood of Poitiers city (France) with families from low socioeconomic and educational status to implement the intervention. However, the ethnographic study noted exclusion of the most vulnerable populations. It appeared that the intervention had omitted a thorough diagnosis of its needs within a given territory.

Implementation
The qualitative study showed that the workshops offered a friendly and dynamic atmosphere, which fostered exchanges. The adaptability of workshop facilitators was appreciated by the participants. Indeed, a great deal of information-sharing, and a lot of interaction occurred in a convivial atmosphere. The participants considered the contents highly practical and concrete. They said they had initiated some changes. The key features of program delivery seemed to be respected with adaptations made during delivery to meet the specific needs of participants. While the objectives of the workshops appeared clear and sufficient, they were perceived as too numerous. The contents in the contextualized place seemed clear and accessible, reassuring, and not guilt-inducing.

Efficacy: RCT Results
After randomization, three participants declined to participate. We excluded three other participants because of missing data. Most analyses were carried out on data from 230 participants: 78 randomized in control group (Group 1) and 152 in intervention groups (Group 2 + 3). Figure 1 shows the flow chart of PREVED study.
All participants were in a relationship; their average age was 33 years. A minority was in precarious situations (10.3% in Group 1 and 14.5% in Group 2 + 3). Table 1 presents socio-demographic data. Table 4 presents the results of the Q1 analysis. Consumption in 2nd (first visit) and 3rd (second visit) trimester between Group 1 and Group 2 + 3 was different for preserved sweetcorn (p = 0.02) and for ready-made meals (24.7% versus 9.3%, p = 0.01). We found no significant difference in consumption of total canned food, canned tuna, other canned food, canned drinks, and plastic drink bottles. Table 5 presents the results of the Q2 analysis. We found no significant difference between Group 1 and Group 2 + 3 in risk perception score evolution or overall psychosocial score evolution. However, we noted a positive trend in both control and intervention groups. The subjective knowledge on EDs of Group.1 increased significantly more than Group 2 + 3. alized place seemed clear and accessible, reassuring, and not guilt-inducing.

Efficacy: RCT Results
After randomization, three participants declined to participate. We excluded three other participants because of missing data. Most analyses were carried out on data from 230 participants: 78 randomized in control group (Group 1) and 152 in intervention groups (Group 2 + 3). Figure 1 shows the flow chart of PREVED study.  Table 6 presents the results of the urine ED analysis between 2nd (first visit) and 3rd trimester (second visit). Out of 225 participants who underwent urine measurement, we did not find a significant difference in percentage of women having a decrease of BPA (26% control group versus 24% intervention groups, p = 0.94) or MePB presence (19% control group versus 32% intervention groups, p = 0.09). Supplementary Table S1 presents the comparison results between neutral location (Group 2) and contextualized location (Group 3): no significant difference in ED levels was observed. Supplementary Table S2 presents the comparison results of the colostrum analysis. Out of 147 pregnant women with colostrum measurement, we found a significant difference in percentage of women with BuPB detection between control group and intervention groups (13% versus 3%, p = 0.03).   After imputation by LoQ divides by two sets of censored data, we found no significant differences in mean concentrations of MePB in urine, either in BPA or MePB concentration in colostrum (Table 7). After imputation by kNN-TN, we found no significant differences in mean concentrations of MePB in urine and colostrum, but we found a statistical difference in BPA mean concentrations (Table 7).

Per-Protocol-Analysis
The PP analysis found a significant increase in the evolution of both risk perception score and a significant difference between groups (+15.73 control group versus +21.03 intervention group, p = 0.003) and overall score (+12.39 control group versus +16.2 intervention group, p = 0.02) ( Table 8). Both significant differences were confirmed by a multivariate analysis that included age, educational attainment, and maternal figure. Linear regression found a significant relationship only between intervention groups and scores (data not shown).
We compared mean scores between the three groups (Table 9), and we found the same results with an increase of the risk perception score among each group after intervention: +16.2 in Group 1, +20.3 in Group 2 (neutral location). and +21.4 in Group 3 (contextualized location) (p = 0.02), and an increase of the overall psychosocial score after intervention: +12.7 in Group 1, +16.0 in Group 2 and +16.4 in Group 3 (p = 0.03). We also found that fast-food consumption increased significantly after intervention among 32.7% of the participants of Group 1, versus 10.5% in Group 2 and 5.3% in Group 3 (p = 0.004).
In PP analysis defined by at least one workshop, urine ED analysis (Table 11), we found a significant difference in percentage of women having a decrease of MePB presence (18% Group 1 versus 33% Group 2 + 3, p = 0.04). In Colostrum ED analysis (Table 12), we found a statistical difference in percentage of women having BuPB detection (14% Group 1 versus 1% Group 2 + 3, p = 0.007).

Maintenance
The ITT analysis of consumption outcomes after one year from childbirth found no significant difference. However, we found in PP analysis that 42.7% of participants in intervention group, versus 39% in control group, significantly increased their consumption of canned tuna, and 46% had a stable consumption, versus 36% in control group (p = 0.04).
We found no significant difference for the intervention's impact on the evolution of risk perception (p = 0.19 in ITT analysis and p = 0.58 in PP analysis). However, we found a significant effect of time. The risk perception score increased significantly during the follow-up time Out of 107 pregnant women who underwent urine measurement at one year after childbirth, we found a significant difference in percentage of women having a decrease of MePB presence (17% control group versus 44% intervention group, p = 0.02) in ITT analysis (Table 13) but not in PP analysis (Table 14).        Table 13. Urine biomarkers and exposure: Univariate analysis between 2nd trimester (first visit) and one year (intent-to-treat analysis) in the PREVED study.

Main Results
PREVED is the first intervention research dedicated to perinatal environmental health education in France. The development, implementation, and evaluation of the PREVED project showed interesting results in terms of reach, adoption, and effectiveness.

Reach and Adoption
We noted a lack of social diversity of participants. Despite the specific recruitment strategies through PMI department involved in DisProSe Consortium, the underprivileged population reached was limited.
The choice of collective workshops has many benefits. Peer education is an important health education instrument that facilitates development of new skills, acquisition of experiential knowledge and promotion of health behavior change through experience sharing and social support [24,25].

Effectiveness = Efficacy * Implementation
In the efficacy study, we found an effect on fast-food consumption, on risk perception score, and on MePB presence in urines. In the implementation evaluation, we found that the key features seemed to be carried out.
We did not find any significant effect on canned food consumption. However, the Q1 questions did not specify which kind of food containers. In fact, participants in workshops were encouraged to avoid metal food containers and to replace them by glass jars as much as possible, a point that was not clarified in the leaflet.
A more pronounced fast-food consumption effect was observed in the intervention groups with a major effect in contextualized location (Group 3).
The contextualized intervention was implemented in a pedagogical apartment, which was close to real-life. Home-based educational intervention on health could improve emotional care for chronic patients and their caregivers, especially for groups in precarious situations [26,27]. Likewise, a home-like environment could create added value in health promotion interventions [28,29].
However, we did not find major differences between Group 2 and Group 3. In fact, we noted that the apartment used for contextualized intervention was insufficiently exploited during workshops. The difference between the two intervention groups was consequently small, and our objective of promoting experimental knowledge was not fully attained.
The increased risk perception scores and a significant difference between control group and intervention groups were highlighted. This increase was maintained even more than a year from the intervention. In practice, risk perception represents a major lever and determinant of health behavior and motivation to change [30,31]; elevated risk perception could promote healthier and safer behaviors [32]. This may explain the reduction of the consumption of canned tuna observed in the long-term. Furthermore, both the interaction and sharing of experiences between participants are likely to contribute to favorable evolution. Involvement in health education processes depends largely on social factors such as peer support, especially within existing groups, and choice of a relatively familiar environment [33].
In PP and ITT analysis, a difference in BuPB presence in colostrum between control group and intervention groups was the only one highlighted (13% versus 1%, p = 0,03), as it was not significant for other EDs. In urine, we found no significant decrease between 2nd and 3rd trimesters. There were higher percentages of women having a decrease in MePB presence in the intervention groups, between control group and intervention groups (19% control group versus 32% intervention groups, p = 0.09). For BPA and ClxBPA, intervention failed to demonstrate a reduced detection level. We did not find that contextualization of workshops influenced biomarker levels in urine or colostrum. Urinary BPA detection percentage (43% 2nd trimester) was lower than in studies on pregnant women in France in 2011 (74%) [34] and in 2016 (100%) [35]. That said, among Canadian pregnant women, detected BPA in first trimester was 43% [36]. Concerning colostrum, in our study, BPA was detected at 77%, close to an American study on women who had just given birth [37]. However, comparison to the literature is complicated: detection percentage varies greatly (from 17 to 100%) due mainly to various analytical methods. ClxBPA, which is less studied than BPA, showed detection percentages close to those found in pregnant women of the EDDS cohort [3]. We detected more pronouncedly for 2nd trimester in PREVED study than in EDDS study: MCBPA (57% PREVED versus 34% EDDS), DCBPA (42% versus 34%), TCBPA (21% versus 35%), and TTBPA (31% versus 18%). In colostrum, because of the lipophilic nature and bioaccumulation of ClxBPA, we expected to find higher percentages of detection than those found. They were higher than those of EDDS (MCBPA 46% PREVED versus 18% EDDS, DCBPA 47% versus 23%, TCBPA 66% versus 17%, and TTBPA 51% versus 2%) [3].
Other RCTs aimed at reducing ED exposure through an intervention. A first study carried out in 2011 found a decrease in BPA detection percentages with a canned-foodexcluded-diet in young adult population [11]. Another study, carried out in 2013, did not find any decrease in children and their parents' urinary phthalates and BPA concentrations [13]. Two other studies carried out were aimed at reducing BPA and phthalate exposure in family members or young adult population, by avoiding plastic packaging and canned food. Both showed decreased mean concentrations for BPA in urine, by 66% for family members [12], and by 79% for young adults, respectively [40]. To our knowledge, only one RCT has been carried out in pregnant women in view of reducing phthalate exposure by eating only fresh and organic diet, without finding any decrease [41].

Evaluation Model
We adopted a parallel RCT with randomization at the individual level, with both quantitative and qualitative analyses. Our choices in this PHIR are questionable. Some authors have recommended in complex interventions to choose stepped-wedge cluster randomized trial where clusters are randomly allocated to different sequences, with each sequence defining the timing of cluster switch from the control to the experimental condition [42]. Even if individual randomization is rarely well-adapted to PHIR because interventions of interest are generally delivered at a group level (e.g., schools, health centers, geographical areas) [42], our targeted population (pregnant women) was not an identifiable group, and group contamination was consequently not possible.
Experimental methods for the evaluation of complex interventions, such as RCT, are the reference methods because they seek to determine the effects of the intervention with high internal validity, avoiding confusion bias. The RCT is clearly an option for PHIR [42], even if it has some drawbacks: (i) interventions are often carried out in the same controlled environment, excluding the interaction between intervention and environment from analysis; (ii) the recruited individuals are highly motivated, decreasing external validity [43]; (iii) the focus of the trial is on effectiveness (efficacy), which de facto excludes adaptation factors, targets achieved and institutionalization; (iv) RCTs are also limited for the study of behavioral factors [44] because the outcome is highly dependent on health determinants (individual characteristics, cultural and social environment, and health systems); (v) the standardization of the intervention, as expected in trials, is not favorable from a continuous learning perspective, which requires variation of the intervention [43].
Instead of RCT, some authors propose alternative assessment models such as the "out of control" test method, where only key functions are standardized while the form is adaptive [43] or RCT adaptations such as cluster randomized trials, pragmatic trials, cluster, and pragmatic or non-RCT designs (quasi-experimental, cohort, realistic evaluation, casecohort studies) [17]. These new evaluation models raise questions of feasibility, acceptability, fairness, and sustainability of interventions and their adaptation to the results of qualitative studies, which provide better understanding of how and why we obtain these assessment results [44]. The process studies are largely designed to assess contextual factors and causative mechanisms [18].
We chose the RE-AIM model because it provided a solid framework to assess the implementation of the PREVED project. It enabled simultaneous examination of both participant-level outcome data and detailed organizational and site-level data [45].

Outcome Choice of the Randomized Control Trial
The main outcome was canned food consumption and not biomarker presence or concentration. A pre/post comparison of biomarker presence could have been a relevant primary endpoint, as suggested by a California study in which a diet devoid of deleterious packages for three days led to a significant decrease in urinary concentrations of BPA metabolites from an average of 3.7 to 1.2 ng/mL [12]. However, other studies suggest that urinary BPA concentrations may vary during pregnancy [46][47][48], while urinary PB concentrations are minimally impacted [49]. These studies have not explored changed consumption patterns that may have occurred between two samples. As a result, it is difficult to conclude that changes in urinary concentrations are due solely to the physiology of pregnancy. That is why before/after comparison of biomarker presence in urine, was not the primary outcome in the PREVED study. Colostrum, which begins to form in the middle of pregnancy [50], may be a good biomarker of cumulative pregnancy exposure to lipophilic molecules such as BPA, Clx-BPA, and PBs. However, it is a rare and difficult matrix to collect under the conditions required to avoid BPA contamination (manual sampling, without gloves or breast pumps): only a single sample can be taken. Before/after comparison of biomarker presence in colostrum is impossible. We preferred to choose various outcomes: consumption, psychosocial, and biomarkers with an interdisciplinary contribution of analytical chemistry, social psychology, epidemiology, sociology, and health promotion disciplines.

Construction Consortium
The consortium creation involving the actors in the evaluation system from the construction of the intervention as part of a continuous improvement approach (researchers, field actors, decision-makers) has enabled scientific projects to mature, as recommended [51]. The solution science of the PHIR is strongly embodied in the practices and especially in the ability to support the meeting and sharing between different expertise to promote their hybridization and thereby the production of new expertise and a non-unidirectional transfer of knowledge [52]. However, in the PREVED project, this did not suffice insofar as there was a lack of exchange between partners; it could be called an epistemic misunderstanding [53]. As it is recommended that evaluation should be considered and built at the same time as the intervention itself, the consortium focused too early on the evaluation phase, which appeared too rigid to build an action of environmental health promotion.

Behavior Theory Model
The conception of PREVED workshops was based on the HBM including 12 behavior modification techniques from the 2013 taxonomy of Michie et al. [54]. According to the Medical Research Council, the main components of an intervention include the development of a theoretical model to better understand the change process [18]. Also, it has been interesting in the PREVED project to integrate sociocultural and economic factors [55], particularly social determinants of health and local context [56] using a solid theoretical base and a consistent and rigorous methodology [57].

Diagnosis with Pregnant Women
According to the PREVED sociologic study, the project omitted a thorough diagnosis of our target population of pregnant women's needs. The behavior of pregnant women has been the subject of a normative and stereotypical approach. Despite the qualitative study on 12 women conducted before the cross-sectional study, a deeper exploration of lifestyle should have been performed. In citizen science, co-creation approach is recommended [58].

Public Heath Deployment
As part of evidence-based-health-promotion [59], this study could contribute to health policy deployment of the environmental health intervention in the care pathway during pregnancy. However, while this type of intervention has been disseminated in maternities, there is evidence of its impact. With the PREVED project, we have proposed effective intervention on risk perception and behavior change. To integrate these workshops into the pregnant women's care pathway, it is necessary to involve medical doctors, nurses, and/or midwives. However, preventive medical recommendations of ED exposure avoidance during pregnancy are not yet being followed [60]. Medical doctors are not educating pregnant women on environmental risk prevention [7] because they are essentially focused on infectious biological risks. They also usually have non-specialized experimental knowledge of emergent risks. However, they have recently become increasingly cognizant of these risks [61].
We have previously recommended to educate pregnant women using simple words, taking the time to understand their representations, and questioning them about their knowledge, risk perception, and behavior (pre/post-test). This exchange could employ an educational tool, which could be part of the PREVED© questionnaire to help health professionals [15]. This new tool, which has been informatized in a smartphone via QR code available in general practitioners' (GP) waiting rooms, has been tested and perceived by GPs as useful to initiate a discussion about environmental health with patients [62] That said, we have described and reported on our public health interventions with the TIDieR tool, which like other tools (Astaire, Trend), does not make the distinction between key function (potentially transferable dimensions) and form (dimensions associated with translation with a specific context) proposed by Villeval, who introduced a "key function/implementation/context" model, which makes a distinction between transferable element assessment and context-specific element assessment [63]. This model is the best alternative for transferability insofar as it takes into account the context [64].

Conclusions
The PREVED intervention is the first intervention research dedicated to perinatal environmental health education in France. Results from program adoption at the institutional level, in terms of participant reach and effectiveness (efficacy * implementation), suggest that the program could be widely implemented. However, it is necessary to co-construct the intervention along with a targeted population, which could consist in young women before pregnancy or more broadly, young people. Maintenance evaluation should contribute to the conservation of this intervention in the health pathways.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/ijerph19010070/s1, Table S1: Urine biomarkers and exposure, univariate analysis between 2nd (first visit) and 3rd trimester (second visit), subgroup analysis for contextualized and noncontextualized, intent-to-treat analysis, PREVED study; Table S2: Colostrum biomarkers and exposure in univariate analysis, intention to treat (ITT), PREVED study; Table S3: Urine biomarkers and exposure, univariate analysis between 2nd (first visit) and 3rd trimester (second visit), intervention group with at least two workshops (Per Protocol analysis) PREVED study.  Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. All participants provided written, informed consent. They were free to leave the RCT at any time.
Data Availability Statement: Dataset used for performing statistical analysis could be provided on reasonable request.