Study protocol of guided mobile-based perinatal mindfulness intervention (GMBPMI) - a randomized controlled trial.

BACKGROUND: Psychological distress is a common occurrence among women during the perinatal period. Maternal psychological distress (MPS) can also have a negative influence on neonatal outcomes such as infant health, child development or mother-child interaction. Hence, interventions to improve mental wellbeing during this period are vital. Mindfulness based intervention (MBI) has been found to be effective in reducing psychological distress. Delivery of MBI via the internet, making it accessible and inexpensive, is showing a promising positive effect in reducing psychological distress. A randomized control trial with sufficient power is required to confirm its positive effect among pregnant women. The positive effects of MBI have been found to be associated with heart rate variability (HRV) biofeedback; however, the efficacy of MBI on HRV has been rarely studied among pregnant women. Also, the potential association of HRV with MBI and psychological wellbeing needs further examination. This research aims to test the effectiveness of guided mobile-based perinatal mindfulness intervention (GMBPMI) among pregnant women experiencing psychological distress during the pre- and post-natal period, as well as examining the efficacy of GMBPMI on HRV.
METHOD: This study is a randomized controlled trial that follows a parallel design. Consenting pregnant women in their second trimester (between 12th and 20th week gestation) will be randomly assigned to an intervention group (GMBPMI) or a control group (psychoeducation). The intended sample size is 198, with 99 participants in each group. Three levels of outcomes will be measured at baseline, post intervention in both the intervention and control groups, and at 36-week gestation and five-week postpartum. The primary outcomes include maternal psychological stress, mindfulness and positive appraisal HRV. Secondary outcomes are psychological and physical wellbeing. Tertiary outcomes include obstetric and neonatal outcomes, and social support. Analyses will follow an intention-to-treat method and repeated measures MANOVA will be conducted to compare changes in primary and secondary outcomes. A series of mixed-effects models will be fitted to assess the mediation effects. DISCUSSION: This trial expects to increase understanding of GMBPMI on HRV and psychological wellbeing for pregnant women, with extended support in both pre-and post-natal periods. The study could also potentially provide evidence for delivery of cost-effective and accessible services to pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04876014, registered on 30 March 2021. Protocol Version 1.0., 10 May 2021.

Introduction

Pregnancy, giving birth and becoming a parent are three major life events that happen together. Were it not for the exhilaration of expecting a new life, many women would experience maternal psychological distress due to the naturally occurring physical, emotional and interpersonal changes [1]. MPS refers to the subjective feelings of distress or strain experienced by women during pregnancy [2]. The most common stresses faced by pregnant women include physical health concerns and psychological stress. Physically, they face increased medical and health concerns and physical discomfort during pregnancy. Psychologically, women experience difficulties in navigating a new identity, childbirth-related fear and anxiety, and the pressure of being a ‘perfect mother’ [3-5]. Research has identified many adverse consequences of maternal psychological distress (MPS) related to both mother and child. Some evidence suggests that MPS may be associated with poor obstetric and neonatal outcomes [6-8] including increased maternal obstetric complications such as analgesic use and unplanned caesarean delivery [9, 10]. Furthermore, fetal exposure to MPS can increase the risk of poor neonatal outcomes, including preterm delivery [11], low birth weight [4], low Apgar scores, smaller head circumference and major congenital anomalies [12, 13]. MPS not only affects perinatal maternal and infant health but may also result in poor postpartum mother-child interaction and child development [7, 14]. Recent evidence has also indicated that as well as depression, anxiety during pregnancy is related to developmental and behavioural issues in children [15].

Women in Hong Kong experiences MPS during perinatal period. Mindfulness intervention is increasingly being used to treat symptoms of anxiety, stress and depression [16, 17]. Accumulating evidence has suggested that mindfulness-based intervention (MBI) may be suitable and beneficial for women in coping with physical discomfort and negative emotions or thoughts during the perinatal period [18, 19]. Through mindfulness training, people can increase self-awareness of their emotions, thoughts and sensations, and cultivate curiosity and openness in their experiences without losing themselves in thoughts and feelings. Such skills are considered vital to pregnant women who experience physical discomfort intertwined with their emotions during the perinatal period.

In recent decades, empirical research has suggested the efficacy of MBI in reducing MPS. For example, a meta-analysis of 17 studies of prenatal MBI demonstrated significant pre- and post-improvements of medium effect size in reducing stress and depression [20, 21]. However, there were no significant postnatal improvements in stress and depression or in mindfulness skills for MBI participants versus the control participants [20]. Lau and colleagues [22] suggest a need to implement the intervention in the second trimester and extend the intervention to the third trimester and postnatal to prevent postpartum depression. MBI was also found to be associated with enhanced biological and infant outcomes. Higher maternal mindfulness of women at 22-week gestation significantly predicted a normal, as opposed to low, neonatal birth weight [23]. Van den Heuvel and colleagues [24, 25] showed that maternal mindfulness was negatively correlated with maternal anxiety during pregnancy, and positively associated with fewer infant self-regulation problems, a less difficult temperament, and greater control in infants at ten months old. In a randomized controlled trial examining the efficacy of MBI among pregnant women, Chan [26, 27] found mothers in the MBI group to have lower levels of the “stress hormone” salivary cortisol in the evening, and the infants at five months old had easier temperaments as well as improved positive appraisal. However, the significant effects were only observed among the 56% of participants who practiced mindfulness regularly [28]. Lack of continued motivation was the most common reason reported for giving up the practice, suggesting a need to extend the current MBI from the second trimester of pregnancy to the third trimester and postnatal period.

Previous studies have shown that MBI has led to increased heart rate variability (HRV) as well as decreased blood pressure and cortisol levels [29, 30], suggesting that MBI may have beneficial physiological effects for pregnant women [31]. Most recently, Braeken and colleagues [31] examined 156 pregnant women with self-reported mindfulness, psychological distress and HRV measures. The research highlighted an association between mindfulness and autonomic nerve system (ANS) changes, suggesting that mindfulness improves HRV measures and leads to better social and emotional development in both mother and offspring. However, few randomized controlled trials have been conducted to test the efficacy of MBI on ANS changes in pregnant women.

The present study aims to rigorously evaluate the effectiveness of a guided mobile-based perinatal mindfulness intervention (GMPMI). Specifically, we aim:

to evaluate the effectiveness of GMPMI on psychological distress of women during the perinatal period;

to evaluate the impact of GMPMI on obstetric and neonatal outcomes;

to investigate HRV changes associated with GMPMI and its mediation effect between maternal psychological distress and neonatal outcomes.

Method

Design

The research adopts a parallel-armed, randomized controlled trial (RCT) design. Pregnant women in their second trimester will be recruited through Qualtrics (https://hku.au1.qualtrics.com/jfe/form/SV_2ofenm3v2OeCyJE). Eligible participants will be randomized to receive either the guided mobile-based perinatal mindfulness intervention (GMPMI) or the web-based perinatal psychoeducation program (WPPP). Repeated measures will be taken at four time-points: pre-intervention (T0); on completion of eight weekly PMI in the intervention group or eight weekly PPP on perinatal care in the control group (T1); 36-week gestation (T2); and five-week postpartum (T3).

Setting

This research is based in Hong Kong. Adopting an online intervention mode, the location of the participants will not compromise their eligibility. The study sites will be the current living environment the participants. The participants will receive perinatal psychoeducation and support, which will be deliberated in the later part.

Participants

Adult (age 18 or above) pregnant Chinese women in their second trimester (between 12th and 28th week gestation) will be invited to the study. This is when pregnancy becomes stable. Participants will be recruited from the community through advertisements posted on relevant websites, maternal discussion forums, Facebook and Twitter. The exclusion criteria are: 1) not able to understand Chinese (the intervention will be delivered in Chinese); 2) high-risk pregnancy status (e.g., preterm labor, placental abnormality, multiple gestations, required bed rest, or morbid obesity); and 3) current psychiatric disorders necessitating priority attention (e.g., schizoaffective disorder, bipolar disorder or current psychosis; organic mental disorder or pervasive developmental delay; current substance abuse or dependence; imminent suicide or homicide risk).

A screening interview via telephone or audio-chat will be conducted with each potential participant to assess eligibility as well as to explain the study in detail and to address concerns. The eligible participants will receive consent forms by email and will be asked to return these to the researchers.

Sample size calculation

The previous eastern-based meditation intervention (EBMI) study reported an effect size of 0.44 in reducing prenatal distress and an attrition rate of around 20% [28]. In the proposed study we assume an overall moderate effect size of 0.4 and a conservative attrition rate of 25%. Setting a power at 90%, a significance level of p < .008 (corrected for six primary outcomes), a sample size of 99 per arm is needed for a two-arm repeated measures design (GPower, version 3.1). Thus, the targeted total sample size is 198. Considering this is a web-based intervention, we will consider expanding the sample size to ensure enough statistical power after preliminary data analysis.

Conceptual framework

The study adopts the transactional theory of stress and coping as its underpinning theoretical framework. Transactional theory proposes how people react to stress, and the intensity of the reaction is heavily influenced by the mediating role of appraisal, the cognitive process through which meaning is ascribed to events [32, 33]. By reordering life priorities based upon one’s values and goals and ascribing positive meaning to stressful events, meaning-focused coping helps to restore the resources that influence cognitive appraisals, sustain coping efforts over time and to provide relief from distress [34, 35].

Through continued mindfulness practice, we hypothesize that perinatal women can increase their maternal mindfulness. Increased maternal mindfulness can expand pregnant women’s perceptual awareness and facilitate positive appraisal during the stressful perinatal period, thereby helping to reduce perinatal psychological stress. This is consistent with the results of a previous study, where positive appraisal was found to be significantly increased in a mindfulness group [28]. Moreover, by reducing perinatal psychological stress, the increase of maternal mindfulness is theorized to lead to higher HRV, suggesting increased parasympathetic control. A decrease in perinatal psychological stress can bring about better birth outcomes (obstetric and neonatal) through increased parasympathetic activity. Fig 1 depicts this conceptual model.

Fig 1

Conceptual framework.

The intervention group would show a greater increase in maternal mindfulness and positive appraisal than the control group at T1, T2 and T3.

The intervention group would show a greater reduction in stress and depression than the control group at T1, T2 and T3 and these outcomes would be mediated by the enhancement in positive appraisal.

The intervention group would show a greater increase in HRV than the control group at T1, T2 and T3 and these outcomes would be mediated by the reduction in stress and depression.

The levels of stress and depression would be negatively associated with obstetric and neonatal outcomes at T3 and these correlations would be mediated by HRV.

Randomization and allocation

The participants’ recruitment will proceed on a continual basis so once begun, a random allocation process will be performed weekly. Online interview will be conducted to ensure eligibility. We use computer-based random number generator to assign numbers to the eligible participants. The research assistant will toss the coin to decide the group allocation and ensure allocation concealment. Two research assistants will interview the participants to check eligibility and obtaining consent. One of the two research assistants will assign random number to the participants, and allocate participants to intervention or control group.

Blinding

It is not possible to blind the participants to group allocation for psychological interventions; however, the study purpose will be masked to participants. The study statistician will also be blinded to the group allocation. Participants’ personal identifiers will not be included in the dataset.

Intervention

Participants in the experimental group will receive the GMPMI. A new participant (a pregnant woman in her second trimester) is expected to complete the eight EBMI lessons in eight weeks and practice mindfulness for about 30–60 minutes daily. The eight-session mindfulness-based intervention is developed from the Mindfulness-Based Cognitive Behaviour (MBCT) protocol for pregnant women. It integrated four-immeasurable meditation, including loving-kindness, compassion, appreciative joy, and equanimity meditations. Different themes are introduced to the participants weekly during the intervention period. These themes include ‘deepening capacity for present’, ‘connecting with breath and body’, ‘inner inspection’, ‘raise awareness of your thoughts’, and ‘savouring goodness’. Prompts and guidance for daily mindfulness practice will be sent to each participant through a social media platform. Participants will also be asked to keep a log of their daily mindfulness practice from T0 to T3 using Google Form. An assisting therapist will be available for online support and will initiate a chat every week throughout the intervention period. The chats will focus on participants’ experiences of or difficulties in the mindfulness practice. The assisting therapist will be supervised by an experienced mental health practitioner and a mindfulness teacher.

Control condition

To control for attention and placebo effects, each new participant in the control group will receive a weekly web-based psychoeducation program for perinatal care (WPPP). WPPP is the parallel program this study adopted for the control group. In this program, essential perinatal and postnatal care knowledge are provided to the participants. Neither mindfulness elements nor counseling support will be given. An assisting therapist will also be available for online support and will initiate a chat every week throughout the intervention period. The chats will focus on participants’ experiences of the psychoeducation program.

Measures

The outcome measures of the study are summarized in Table 1, including the detailed time-points at which the measures will be taken. In order to fulfill the study objective, the primary outcome variables include a battery of scales to measure MPS, mindfulness, positive appraisal and HRV. Secondary outcome variables include more general measures of psychological and physical wellbeing. Anxiety is considered as a more general measure which could be influenced by life events other than pregnancy, and is thus included as a secondary measure. To investigate the impact of the intervention on children, clinical obstetric and neonatal outcomes will also be collected. Other individual data such as demographic data and social support levels will be measured. All the questionnaire links will be sent to the participants through WhatsApp at each time-point for them to fill in on their own devices.

Table 1

Outcome variables.

Variables	Measures	Timepoints
Primary outcome variables
Maternal psychological stress
General stress	Perceived Stress Scale –10 items–The scale measures subjective perception of stress with two subscales, perceived helplessness and perceived self-efficacy [36, 37].	T0, T1, T2, T3,
Pregnancy- specific stress	Prenatal Distress Questionnaire– 12 items–The scale consists of three factors–concerns about birth and baby, weight and body image, emotions and relationships [38].	T0, T1, T2
Depression	Edinburgh Postnatal Depression Scale–Chinese– 10 items–The scale has been validated in the Chinese population with satisfactory psychometric properties [39].	T0, T1, T2, T3
Mindfulness
State mindfulness	Short-form Five Facet Mindfulness Questionnaire– 20 items–The scale consists of five subscales–observing, describing, acting awareness, non-judging of inner experience and non-reacting to inner experience [40].	T0, T1, T2, T3
Daily mindfulness	Daily Mindful Responding Scale– 4 items–A measure designed to assess mindful responding in the daily lives of people undergoing mindfulness training [41].	Every week until T3
Positive appraisal
Coping	Prenatal Coping Inventory– 22 items–consists of four subscales–preparation, avoidance, positive appraisal and prayer [42].	T0, T1, T2
Heart rate variability
HRV Index	CorSense by Elite HRV–A merchandise device monitoring heart rate variability	T0, T1, T2, T3
Secondary outcome variables
Psychological wellbeing
Anxiety	Short-form State subscale of the State-Trait Anxiety Inventory– 6 items—The scale has been validated in pregnant women with satisfactory psychometric properties [43].	T0, T1, T2, T3,
Affect	Positive & Negative Affect Subscales of Body-Mind-Spirit Wellbeing Inventory– 8 and 16 items—The two subscales measure common positive and negative affect in Chinese adults [44].	T0, T1, T2, T3,
Spirituality	Chinese Daily Spiritual Experience Scale– 16 items–The scale measures a person’s perception of transcendence involvement in daily life [45, 46].	T0, T1, T2, T3,
Physical wellbeing
Stagnation	Stagnation Scale– 16 items—The scale measures a cluster of mind and body obstruction-like symptoms depicted in Chinese medicine. It has three factors: body/mind obstruction, affect/posture inhibition, and overattachment [47, 48]. Stagnation was identified as a mediator in explaining the mechanism of change in mindfulness [49].	T0, T1, T2, T3,
Clinical outcomes
Obstetric outcomes	Gestational age at birth, pregnancy complications, mode of birth.	T3
Neonatal outcomes	Birth weight, head circumference, months of maturity, Apgar score.	T3
Individual factors
Socio-demographic	Age, gender, marital status, family income, employment, education, gestational age, parity, obstetric history, medical history, pre-pregnancy BMI.	T0
Social support	Prenatal Social Support– 4 items–The scale measures the level of social support women receive during pregnancy [50].	T0, T1, T2

HRV index will be collected through CorSense device. This device is designed as a finger clip which is portable and easy for the pregnant women to use. HRV scores will be calculated automatically. The higher HRV score indicates a better mental health status. The calculation of HRV score is based on the components of the HRV measurements. The R-R intervals will be captured through the Corsense monitor, followed by an industry standard RMSSD calculation. After applying a natural log (ln) to RMSSD, HRV score is conceptualized with a magnitude ranging from 0 to 100. In the meantime, the Corsense device can also capture the raw data of standard deviation of NN intervals (SSDN), the root mean square of the successive difference (rMSSD) in R-R intervals, and low frequency (LF), high frequency (HF), and very low frequency (VLF). This can serve as complementary data for the research team to do data analysis. Elite HRV provides a Team Dashboard for the research team to manage the participants’ data in a more convenient way. All the HRV scores and raw data will be sent to the Team Dashboard once the participant completed the measurement.

Data management plan

HYL and AW will be responsible for data collection under the supervision of SMN, the principal investigator of this research project. All digital data, including questionnaires, consent forms and HRV index data will be stored as a data package in an encrypted hard drive, strictly following the data management guidelines of the University of Hong Kong. Identifiable personal data will be stored separately from the anonymous data to avoid identification of personal data during handling. Participants’ confidentiality will be protected by following the ethics guidelines of the Human Research Ethic Committee of the University of Hong Kong.

Data will be analyzed by HYL and AW after the completion of all stages of data collection without interim data analysis. Data will not be shared before the completion of the research project. Data will be available upon request to the corresponding author after the completion of the study.

Safety considerations

To our knowledge, there are no safety issues for pregnant women in practicing mindfulness or receiving maternal and neonatal care education. A safety exercise review will be provided for participants during the intake interview and will include the local GP contact, project staff contact and suggestions of a safe place to practice. The participants will be encouraged to report any adverse events occurring during practice as soon as possible by WhatsApp. We also have an experienced obstetrics and gynaecology specialist to provide advice to the participants as required to ensure their safety. Any adverse events will be reported by the principal investigator to the Human Research Ethics Committee at the University of Hong Kong using an adverse event report.

Ethical consideration and declarations

This trial was approved by the Human Research Ethics Committee of the University of Hong Kong (HREC Reference No.: EA1812034). Participants assigned to the intervention group will be voluntarily participate in the current trial. Participants assigned to the control group will receive the psychoeducation program (treatment as usual). Online written informed consent will be provided to the participants in both intervention and control groups after being informed in writing about the study. Participants from both intervention and control groups will fill out questionnaires as listed in the measure part of the article.

Data analysis

Quantitative data including scale measures and the HRV index will be collected at four time-points as articulated above.

Intention-to-treat analysis will be performed and missing data due to drop–out will be handled by the ‘multiple imputation’ technique [51]. 1) Using a two-arm RCT design, the efficacy of the intervention will be examined by repeated measures MANOVA on both the primary and secondary outcome variables, while adjusting for individual factors. Partial eta-squared values will be calculated to measure the effect size; values of .02, .13 and .26 suggest small, medium, and large effect sizes, respectively [52]. 2) To investigate the within-group effect, serial trend analysis from T0 to T3 will be conducted on the primary and secondary outcome variables. 3) A series of linear mixed-effects models will be fitted to assess the mediation effects. 4) The software Elite HRV Team Dashboard will be used for HRV data collection. Three HRV indexes will be computed for analysis, namely RMSSD (Mean squared difference between consecutive normal-to-normal intervals), SDNN (standard deviation of beat-to-beat intervals) and HF (absolute power of HF band).

Data monitoring

Considering the timeframe and the minimal risk known to the participants of the current study, the Data Monitoring Committee was not formed [53]. The research team will continue monitoring the needs of forming such team.

Strategies for improving adherence

Participants will be requested to take an HRV measure after everyday mindfulness practice. The measurements will be collected through a computer software Elite HRV Team Dashboard, allowing the research assistant (RA) to track the adherence of each participant. For those participants who failed to practice mindfulness, the RA will send a reminder through WhatsApp.

Trial status and timeline

The tentative schedule of the research is shown in the Figs 2 and S1. As of 15 April 2021, the study team is preparing the research materials, with recruitment expected to start in May. Intervention and data collection is expected to be completed by May 2022. Data analysis and report writing will be completed by the end of December 2022. Any amendment or deviation from the protocol will be reported to the Human Research Ethics Committee at the University of Hong Kong by submitting an application for amendment of an approved project form in hardcopy.

Fig 2

SPIRIT schedule of enrolment, intervention and assessments.

Note: -t1, 0, baseline; t1, post 8-week intervention; t2, 36-week gestation follow up; t3. 5-week postpartum follow up.

Discussion

The study’s objective is to test the efficacy of GMBPMI in improving mindfulness and positive appraisal, and reducing pregnant related stress and depression. As a possible mediator, HRV will also be examined to confirm the efficacy of GMBPMI on ANS changed among pregnant women. Additionally, trajectory of maternal psychological distress will also be examined in relation to obstetric and neonatal outcomes at 5-week postpartum period. In line with the research objectives, the primary outcomes of the research are changes in maternal psychological distress, mindfulness, positive appraisal and the HRV index. The secondary outcomes are general psychological and physical wellbeing, such as anxiety, affect, spirituality and stagnation. The clinical outcomes include obstetric and neonatal outcomes, such as gestational age at birth, pregnancy complications, mode of birth, infant Apgar score and head circumference.

This study has both strengths and limitations. Strengths include the randomized controlled trial study design with a large sample size of 198 to ensure sufficient power to demonstrate the efficacy of GMBPMI intervention. More importantly, the research stands out in its innovative delivery mode. Delivered through mobile devices, this study is an extension of the previous face-to-face EMBI intervention, making it feasible for pregnant women to practice at home. Furthermore, this study is one of the few research projects to examine not only psychological but also physiological changes (e.g., HRV), allowing us to detect the potential mediation effect of HRV on GMBPMI and psychological wellbeing. A limitation of this study is that participants in the control group might seek other services or interventions similar to MBI to improve their psychological wellbeing, potentially leading to difficulties in detecting the group difference. To deal with such contamination, we will collect data of any alternative treatments the participants are taking.

A significant part of the current study is that the results of the research (reducing maternal psychological distress by GMBPMI) are to be disseminated not only in Hong Kong SAR but also internationally. Hence, we propose the following approach: Upon completion of the study, our research team will seek to publish the data output in international peer reviewed scientific journals, as well as disseminating the results through presentations at local and international conferences. The research material will be further refined by reflecting on the obstacles during the intervention procedure. A guideline booklet will be generated for the general public to use. Furthermore, with the success of this research, it is expected that the whole program will be promoted through the hospital authority to private clinics and public hospitals as supportive resources for pregnant women. All the materials are expected to be accessed through online platforms either on the Department of Health website by the government of the Hong Kong Special Administrative Region Family Health Service—Home (fhs.gov.hk), or through a privately created webpage by the research team.

CONSORT diagram.

(TIFF)

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(DOCX)

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SPIRIT checklist.

(PDF)

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All items from the World Health Organization Trial Registration Data Set.

(PDF)

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17 Feb 2022

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Reviewer #1: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that (such) study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related & intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance]. To improve the article/presentation, clues/hints may be taken from this review but should not limit the process by adhering to those points alone.

COMMENTS: Please refer to section on ‘Sample size calculation’ where it is said that “The previous eastern-based meditation intervention (EBMI) study reported an effect size of 0.44 in reducing prenatal distress” but a reference is not quoted. Therefore, which previous [eastern-based meditation intervention (EBMI)] study authors are referring to is not clear. This is important because the ‘effect size’ of 0.44 [in reducing prenatal distress] used for required ‘Sample size’ calculations here [even overall moderate effect size of 0.4] is too large in my opinion as in such studies ‘effect size’ achieved is generally small and therefore, you need a large sample. Moreover, since the entire study is ‘via telephone or audio-chat / web-based’, “power achieved” is likely to be smaller than intended.

Agreed that ‘Blinding’ is not possible for psychological interventions; however, I wonder if ‘waitlisting controls’ be useful {to some extent}? In addition, please note the following:

Though the measures/tools used are appropriate [Table 1. Outcome variables], most of them yield data that are in [at the most] ‘ordinal’ level of measurement [and not in ratio level of measurement for sure {as the score two times higher does not indicate presence of that parameter/phenomenon as double (for example, a Visual Analogue Scales VAS score or say ‘depression’ score)}]. Then application of suitable non-parametric test(s) is/are indicated/advisable [even if distribution may be ‘Gaussian’ (i.e. normal)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s) [suitable / most desired/applicable], but should be used whenever/wherever they are available.

This is not to say that what is proposed to be used here [Analyses will follow an intention-to-treat method and repeated measures MANOVA will be conducted to compare changes in primary and secondary outcomes] is not correct. In fact, this is most indicated. Since this is a ‘Study protocol’, note this fact in addition to think of ‘change score(s)’. Also note that ‘repeated measures MANOVA’ need/s to be followed by ‘multiple comparison(s)’ with appropriate adjustment in P-value(s).

Is the imputation method proposed [missing data due to drop–out will be handled by the ‘last observations carried forward’ principle] is suitable for this situation? Since missing data are to be imputed using the ‘last observation carried forward’, I hope the authors are aware of disadvantages [like this method assumes that the response remains constant at the last observed value. This assumption can be biased if the timing and the rate of withdrawal is related to the treatment (e.g. in the case of degenerative diseases, using the last observed value to impute for missing data at a later point in the study means that a higher observation will be carried forward, resulting in an overestimation of the true end-of study measurement)] of the method (must be known to these learned authors, still may please be noted) that:

“according to available literature [example, “Inference and Missing Data,” Biometrika, 1976, vol:63, 581–592 and “Multiple Imputation After 18+ Years,” Journal of the American Statistical Association, 1996, vol:91, 473–489] ‘Multiple Imputation’ technique is preferred [considering MCAR (Missing Completely At Random) expected nature of data] than {despite being time-consuming and involving much more computations} compare to all out of other important imputation techniques frequently used [like Group Means, Hot-deck Imputation, Baseline Observation Carried Forward (BOCF), Worst Observation Carried Forward (WOCF), Predicted Mean, and even Last Observation Carried Forward (LOCF)].”

Except these few points, this protocol manuscript appears to be alright.

Reviewer #2: The manuscript is about a study protocol of guided mobile-based perinatal mindfulness intervention (GMBPMI) for pregnant women. But the manuscript doesn’t follow the checklist of SPIRIT 2013 strictly which defining standard protocol items for clinical trials.

1."Maternal psychological distress (MPS) " needs to be defined. This not a term in common use.

2.Why the author recruited pregnant women in their second trimester as participants? Does the pregnant women who attending the study complicate with maternal psychological distress?

3.What the differences between mobile-based and web based? (From the sentence: Eligible participants will be randomized to receive either the guided mobile-based perinatal mindfulness intervention (GMPMI) or the webbased perinatal psychoeducation program (WPPP)).

4. Why the participants in control need to receive web-based psychoeducation program?

What kinds of strategies for psychological counseling will be used for women in control group?

5.Where was the study being conducted? The author did not describe study setting in detaile.

6. How do the author generate the allocation sequence? Is there any measure to conduct the allocation concealment?

7. Who will generate the allocation sequence, who will enroll participants, and who will assign participants to interventions?

8. Why anxiety was defined as the second outcome rather than the first outcome?

9. How to evaluate HRV? What is the difference between CorSense by Elite HRV and KardaMobile ECG ?

10. What is the content for eight weekly interventions? Is there any difference among each session?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

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7 Mar 2022

Dear Dr. Shepherd and Reviewers,

We are very glad to receive a positive editorial decision and we appreciated your time to provide us with thoughtful and insightful feedbacks and comments on this study protocol. After thoroughly reviewing your feedbacks and comments, we would like to take this opportunity to further improve our manuscript. Some misunderstandings which might be due to the poor presentation of the manuscript will also be clarified. The following shows the point-to-point response to both reviewers’ comments and questions. Full text of each editor’s and reviewer’s comments are copied as below. Each point will be followed with a reply immediately. The manuscript is also carefully revised based on the reviewers’ comments. Files of 'Response to Reviewers', 'Manuscript', 'Revised Manuscript with Track Changes' are attached to this submission for your further review.

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Reply

The manuscript and file names are edited to meet PLOS One’s style requirements. Please refer to the newly submitted manuscripts.

2. Thank you for stating the following financial disclosure: "This research received

General Research Fund funding scheme (17603520) from Research Grants Council, Hong Kong SAR. SMG is the principal investigator of this research project. The funders had and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. "

We note that one or more of the authors is affiliated with the funding organization, indicating the funder may have had some role in the design, data collection, analysis or preparation of your manuscript for publication; in other words, the funder played an indirect role through the participation of the co-authors. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please do the following:

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“The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

Reply

The funding organization did not play a role in the study design, data collection and analysis, decision to publish or preparation manuscript. Only financial support was provided in forms of author Amenda Wang’s salary and research materials. The statement in section b is included in the cover letter.

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manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

Reply

The ethics statement section is moved to the Methods section.

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figure is no longer to be included as part of the submission please remove all reference to it within the text.

Reply

The Figure 2 is changed to S2 Fig both in the manuscript and under the Supporting documents section. Both S1 and S2 Figs will be uploaded to the online platform.

Reviewer #1

Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that (such) study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related & intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance]. To improve the article/presentation, clues/hints may be taken from this review but should not limit the process by adhering to those points alone.

COMMENTS: Please refer to section on ‘Sample size calculation’ where it is said that “The previous eastern-based meditation intervention (EBMI) study reported an effect size of 0.44 in reducing prenatal distress” but a reference is not quoted. Therefore, which previous [eastern-based meditation intervention (EBMI)] study authors are referring to is not clear. This is important because the ‘effect size’ of 0.44 [in reducing prenatal distress] used for required ‘Sample size’ calculations here [even overall moderate effect size of 0.4] is too large in my opinion as in such studies ‘effect size’ achieved is generally small and therefore, you need a large sample. Moreover, since the entire study is ‘via telephone or audio-chat / web-based’, “power achieved” is likely to be smaller than intended.

Reply

Thank you for the comments and sharing your opinion about statistical power in conducting web-based intervention. The reference regarding EBMI study [28] is now quoted in the manuscript (also listed below for your easy reference). The suggestion of adopting a larger sample is taken. The target sample size of 198 is believed to be conservative enough. We will consider expanding the sample size to ensure enough statistical power after preliminary data analysis.

28. Chan KP. Effects of perinatal meditation on pregnant Chinese women in Hong Kong: a randomized controlled trial. Journal of Nursing Education and Practice. 2015; 5(1): 1.

Agreed that ‘Blinding’ is not possible for psychological interventions; however, I wonder if ‘waitlisting controls’ be useful {to some extent}?

Reply

Waitlisting control is not feasible in the current study because the targeted participants are in their second trimester of pregnancy. Upon completion of intervention and follow-up measures in the experimental group, participants in the waitlist control group should have already delivered their baby.

In addition, please note the following:

Though the measures/tools used are appropriate [Table 1. Outcome variables], most of them yield data that are in [at the most] ‘ordinal’ level of measurement [and not in ratio level of measurement for sure {as the score two times higher does not indicate presence of that parameter/phenomenon as double (for example, a Visual Analogue Scales VAS score or say ‘depression’ score)}]. Then application of suitable non-parametric test(s) is/are indicated/advisable [even if distribution may be ‘Gaussian’ (i.e. normal)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s) [suitable / most desired/applicable], but should be used whenever/wherever they are available.

Reply

Agreed that non-parametric test is worth considering whenever it is needed. We will take this point into consideration while conducting data analysis.

This is not to say that what is proposed to be used here [Analyses will follow an intention-to-treat method and repeated measures MANOVA will be conducted to compare changes in primary and secondary outcomes] is not correct. In fact, this is most indicated. Since this is a ‘Study protocol’, note this fact in addition to think of ‘change score(s)’. Also note that ‘repeated measures MANOVA’ need/s to be followed by ‘multiple comparison(s)’ with appropriate adjustment in P-value(s).

Is the imputation method proposed [missing data due to drop–out will be handled by the ‘last observations carried forward’ principle] is suitable for this situation? Since missing data are to be imputed using the ‘last observation carried forward’, I hope the authors are aware of disadvantages [like this method assumes that the response remains constant at the last observed value. This assumption can be biased if the timing and the rate of withdrawal is related to the treatment (e.g. in the case of degenerative diseases, using the last observed value to impute for missing data at a later point in the study means that a higher observation will be carried forward, resulting in an overestimation of the true end-of study measurement)] of the method (must be known to these learned authors, still may please be noted) that:

“according to available literature [example, “Inference and Missing Data,” Biometrika, 1976, vol:63, 581–592 and “Multiple Imputation After 18+ Years,” Journal of the American Statistical Association, 1996, vol:91, 473–489] ‘Multiple Imputation’ technique is preferred [considering MCAR (Missing Completely At Random) expected nature of data] than {despite being time-consuming and involving much more computations} compare to all out of other important imputation techniques frequently used [like Group Means, Hot-deck Imputation, Baseline Observation Carried Forward (BOCF), Worst Observation Carried Forward (WOCF), Predicted Mean, and even Last Observation Carried Forward (LOCF)].”

Reply

Thank you for your mindful suggestion. Apart from LOCF, we will also use Multiple Imputation/ Hot-deck Imputation to treat missing data, depending on the characteristics of our missing data.

Except these few points, this protocol manuscript appears to be alright.

Reviewer #2

The manuscript is about a study protocol of guided mobile-based perinatal mindfulness intervention (GMBPMI) for pregnant women. But the manuscript doesn’t follow the checklist of SPIRIT 2013 strictly which defining standard protocol items for clinical trials.

1."Maternal psychological distress (MPS) " needs to be defined. This not a term in common use.

Reply

Maternal psychological stress refers to the subjective feelings of distress or strain experienced by mothers during their pregnancy.

2.Why the author recruited pregnant women in their second trimester as participants? Does the pregnant women who attending the study complicate with maternal psychological distress?

Reply

During the second trimester, women in pregnancy are in stable period, and have the capacity to participate in the intervention program. Previous studies have suggested that intervention in the second trimester might be useful to prevent postpartum depression. Hence, we recruited pregnant women in their second trimester as our participants.

We did not include maternal psychological distress as part of our inclusion and exclusion criteria. Previous research suggested maternal psychological distress is commonly observed among pregnant women in their second and third trimester. Our research aims to investigate the prevention effectiveness of GMBPMI on the maternal psychological distress.

3.What the differences between mobile-based and web based? (From the sentence: Eligible participants will be randomized to receive either the guided mobile-based perinatal mindfulness intervention (GMPMI) or the webbased perinatal psychoeducation program (WPPP)).

Reply

The main difference between GMPMI and WPPP is the content of the program. GMPMI is a mindfulness-based intervention delivered through mobile phone by using WeChat mini program, and thus it is described as a mobile-based perinatal mindfulness intervention. WPPP is the parallel program this study adopted for the control group. In this program, only psychoeducation content is used, without any mindfulness practice elements. WPPP program is uploaded to an online platform called Youku, where the participants will watch the video clips produced by our team. That’s why we name this program a web-based perinatal psychoeducation program. Since psychoeducation is something basic and essential to women in pregnancy, WPPP will also be provided to the intervention group participants.

4. Why the participants in control need to receive web-based psychoeducation program? What kinds of strategies for psychological counseling will be used for women in control group?

Reply

The psychoeducation program includes essential maternal and perinatal care knowledge. It is a general education for the pregnant women to take care of themselves and their newborn babies. The program does not include psychological counselling elements.

Another reason to provide WPPP to control group is to ensure motivation for our participants to join the research study. From WPPP they will receive information, which is also beneficial but distinguished from GMPMI program.

5.Where was the study being conducted? The author did not describe study setting in detail.

Reply

The study team is based in Hong Kong, and uses the local dialect in delivering the intervention. Practically participants will speak local Hong Kong dialect, and be mostly residing in Hong Kong.

6. How do the author generate the allocation sequence? Is there any measure to conduct the allocation concealment?

Reply

After checking eligibility and obtaining consent from the participants through online interview, we use computer-based random number generator to assign each participant a number. The research assistant will toss the coin to decide the group allocation before the study. The research assistant will not know the group allocation before the study. This assures allocation concealment.

7. Who will generate the allocation sequence, who will enroll participants, and who will assign participants to interventions?

Two research assistants will interview the participants to check eligibility and obtain informed consent. One of the two research assistants will assign random number to the participants, and assign participants to intervention or control group.

8. Why anxiety was defined as the second outcome rather than the first outcome?

Reply

In this study, our focus is on the pregnancy-related distress. The primary outcomes include stress and depressive symptoms which are stressor (pregnant) related. Anxiety is more general, including persistent, excessive worries without an obvious stressor. Anxiety could be influenced by other adverse life events other than pregnancy. Hence, we put anciety as a secondary outcome.

9. How to evaluate HRV? What is the difference between CorSense by Elite HRV and KardaMobile ECG?

Reply

HRV will be collected by using the CorSense device. This device is designed as a finger clip which is portable and easy for the pregnant women to use. The other reason is that HRV scores will be calculated automatically. The higher HRV score indicates a better mental health status. The calculation of HRV score is based on the components of the HRV measurements. First, the R-R intervals will be captured through the Corsense monitor. Then, RMSSD calculation, as an industry standard is applied. A natural log (ln) is applied to RMSSD to conceptualize its magnitude. Last, the ln(RMSSD) is expanded to general score ranging from 0 to 100. In the meantime, the Corsense device can also capture the raw data of standard deviation of NN intervals (SSDN), the root mean square of the successive difference (rMSSD) in R-R intervals, and low frequency (LF), high frequency (HF), and very low frequency (VLF). This can serve as complementary data for the research team to do data analysis. Moreover, Elite HRV provides a Team Dashboard for the research team to manage the participants’ data. All the HRV scores and raw data will be sent to the Team Dashboard once the participant completed the measurement.

KardaMobile ECG captures the raw ECG that requires the research team to do the calculation. Since our intervention is delivered online, our participants will need to report their data frequently to the research team. Since there is no such function that the data could be automatically transferred to a computer terminal, it is not feasible for the research team to collect and manage the data remotely. Requesting the participants, who are pregnant, to report and capture the ECG raw data to the research team might reduce their compliance to the study. Bias could also arise from this.

10. What is the content for eight weekly interventions? Is there any difference among each session?

Reply

The eight-session mindfulness-based intervention is developed from the Mindfulness-Based Cognitive Behaviour (MBCT) protocol for pregnant women. It integrated four-immeasurable meditation, including loving-kindness, compassion, appreciative joy, and equanimity meditations. Different themes are introduced to the participants weekly during the intervention period. These themes include ‘deepening capacity for present’, ‘connecting with breath and body’, ‘inner inspection’, ‘raise awareness of your thoughts’, and ‘savouring goodness’.

Thank you very much for all your time and considerate comments and feedbacks. We look forward to having further knowledge exchange with you. Should you have further comments, please feel free to contact us.

Best regards,

Hui Yun Li

erinhy@connect.hku.hk

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

16 Jun 2022

Study protocol of guided mobile-based perinatal mindfulness intervention (GMBPMI) - a randomized controlled trial

PONE-D-21-16157R1

Dear Dr. Li,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

We noticed that there are some language and grammar errors remaining, and we thus request that you fully copyedit the manuscript before submitting the final version.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Staff Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: COMMENTS: Since all of the comments made on earlier draft by me (and hopefully by other respected reviewers also) were/are attended positively, I recommend the acceptance because the manuscript now has achieved acceptable level, in my opinion.

**********

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Reviewer #1: Yes: Dr. Sanjeev Sarmukaddam

**********

28 Jun 2022

PONE-D-21-16157R1

Study protocol of guided mobile-based perinatal mindfulness intervention (GMBPMI) - a randomized controlled trial

Dear Dr. Li:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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