Reductions in Biopsychosocial Risks for Pregnant Latina Women and Their Infants: The Mastery Lifestyle Intervention (MLI)
Phase: NA
Conditions: Mental Health Wellness 1, Preterm Birth
Sponsor: Microgen LLC

 
 
 
 
Reductions in Biopsychosocial Risks for Pregnant Minority Women 
and Their Infants:  
The Mastery Lifestyle Intervention 
 
 
 
 
 
Protocol Number: #20235111 
National Clinical Trial (NCT) Identified Number: NCT05012072   
Principal Investigator: R. Jeanne Ruiz, PhD, WHCNP-BC, FAAN 
Sponsor: Microgen Laboratories, LLC 
Grant Title: Reductions in Biopsychosocial Risks for Pregnant Minority 
Women and Their Infants: The Mastery Lifestyle Intervention 
Grant Number: R01 HD101535-01A1 
Funded by: NIH National Institute of Child Health and Human Development 
Version Number:  v. 5.1 
9-16-2024

 
 
 
 
Table of Contents 
STATEMENT OF COMPLIANCE .............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE ............................................................................................................................... 2 
1.1 
Synopsis ................................................................................................................................................. 3 
1.2 
Schema (See Next Page) ........................................................................................................................ 5 
1.3 
Schedule of Activities ............................................................................................................................ 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale and background .......................................................................................................... 13 
2.2 
Risk/Benefit Assessment ...................................................................................................................... 20 
2.2.1 
Known Potential Risks ..................................................................................................... 20 
2.2.2 
Known Potential Benefits ................................................................................................. 21 
2.2.3 
Assessment of Potential Risks and Benefits ..................................................................... 21 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 24 
4 
STUDY DESIGN ............................................................................................................................................ 25 
4.1 
Overall Design ...................................................................................................................................... 25 
4.2 
Scientific Rationale for Study Design .................................................................................................. 29 
4.3 
Justification for Intervention ................................................................................................................ 29 
4.4 
End-of-Study Definition ....................................................................................................................... 29 
5 
STUDY POPULATION ................................................................................................................................. 30 
5.1 
Inclusion Criteria .................................................................................................................................. 30 
5.2 
Exclusion Criteria ................................................................................................................................. 30 
5.3 
Lifestyle Considerations ....................................................................................................................... 31 
5.4 
Screen Failures ..................................................................................................................................... 31 
5.5 
Strategies for Recruitment and Retention ............................................................................................. 31 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) .............................................. 34 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration .............................................. 34 
6.1.1 Study Intervention or Experimental Manipulation Description .................................................................. 34 
6.1.2 Administration and/or Dosing .................................................................................................................... 35 
6.2 
Fidelity ................................................................................................................................................. 35 
6.2.1 Interventionist Training and Tracking ........................................................................................................ 35 
6.3 
Study Intervention/Experimental Manipulation Adherence ................................................................. 37 
6.4 
Concomitant Therapy ........................................................................................................................... 37 
6.4.1 Rescue Therapy 37 
7. 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION 
AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ............................................................................... 37 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ..................................................... 37 
7.2 
Participant Discontinuation/Withdrawal from the Study...................................................................... 38 
7.3 
Lost to Follow-Up ................................................................................................................................ 38 
8. 
STUDY ASSESSMENTS AND PROCEDURES .......................................................................................... 39 
8.1 
Endpoint and Other Non-Safety Assessments ...................................................................................... 39 
8.2 
Safety Assessments .............................................................................................................................. 41 

 
 
 
 
8.3 
Adverse Events and Serious Adverse Events ....................................................................................... 42 
8.3.1 
Definition of Adverse Events ........................................................................................... 42 
8.3.2 
Definition of Serious Adverse Events ............................................................................... 42 
8.3.3 
Classification of an Adverse Event ................................................................................... 42 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ................................. 43 
 
8.3.5 
Adverse Event Reporting .................................................................................................. 45 
8.3.6 
Serious Adverse Event Reporting ..................................................................................... 45 
8.3.7 
Reporting Events to Participants ....................................................................................... 45 
8.3.8 
Events of Special Interest ................................................................................................. 46 
8.3.9 
Reporting of Pregnancy .................................................................................................... 46 
8.4 
Unanticipated Problems ....................................................................................................................... 46 
8.4.1 
Definition of Unanticipated Problems .............................................................................. 46 
8.4.2 
Unanticipated Problems Reporting ................................................................................... 46 
8.4.3 
Reporting Unanticipated Problems to Participants ........................................................... 47 
9. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 47 
9.1 
Statistical Hypotheses ........................................................................................................................... 47 
9.2 
Sample Size Determination .................................................................................................................. 47 
9.3 
Populations for Analyses ...................................................................................................................... 48 
9.4 
Statistical Analyses............................................................................................................................... 49 
9.4.1 
General Approach ............................................................................................................. 49 
9.4.2 
ANALYSIS OF THE PRIMARY ENDPOINTS .............................................................. 49 
9.4.3 
Analysis of the SECONDARY Endpoint(s) ..................................................................... 50 
9.4.4 
Safety Analyses ................................................................................................................ 50 
9.4.5 
Baseline Descriptive Statistics .......................................................................................... 50 
9.4.6 
Planned Interim Analyses ................................................................................................. 51 
9.4.7 
Sub-Group Analyses ......................................................................................................... 51 
9.4.8 
Tabulation of Individual Participant Data ......................................................................... 51 
9.4.9 
Exploratory Analyses ........................................................................................................ 51 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .................................. 51 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ................................................................... 51 
10.1.1 
Informed Consent Process ................................................................................................ 51 
10.1.2 
Study Discontinuation and Closure .................................................................................. 65 
10.1.3 
Confidentiality and Privacy .............................................................................................. 66 
10.1.4 
Future Use of Stored Specimens and Data........................................................................ 67 
10.1.5 
Key Roles and Study Governance .................................................................................... 67 
10.1.6 
Safety Oversight ............................................................................................................... 70 
10.1.7 
Clinical Monitoring .......................................................................................................... 70 
10.1.8 
Quality Assurance and Quality Control ............................................................................ 70 
10.1.9 
Data Handling and Record Keeping ................................................................................. 71 
10.1.10 
Protocol Deviations  and publication and data sharing policy .......................................... 72 

 
 
 
 
10.1.11 
Conflict of Interest Policy ................................................................................................. 73 
10.2 
Additional Considerations .................................................................................................................... 73 
10.3 
Abbreviations and Special Terms ......................................................................................................... 73 
10.4 
Protocol Amendment History ............................................................................................................... 76 
11. 
REFERENCES................................................................................................................................................ 78 
 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812).  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the IRB for review and approval. Approval of both the protocol and 
the consent form(s) must be obtained before any participant is consented. Any amendment 
to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. All changes to the consent form(s) will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable US federal regulations and ICH guidelines, as described in the Statement of Compliance 
above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
9-16-2024 
 
Name: Roberta Jeanne Ruiz 
 
Title: Primary Investigator/Principal Health Research Scientist Microgen Laboratories 
 
Investigator Contact Information 
Affiliation: Microgen Laboratories, LLC 
Address: 7580 Fannin Street Suite 303 
Houston Texas USA 77054 
Telephone: 281-300-5265 
Email: jruiz@microgenlabs.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.1 
SYNOPSIS  
 
Title: 
Reductions in Biopsychosocial Risks for Pregnant Latinas and 
Their Infants: The Mastery Lifestyle Intervention 
Grant Number: 
R01 HD101535-01A1-02 
Study Description: 
To address the gaps related to interventions for minority (Hispanic 
and African American) pregnant women, we have developed and 
successfully pilot tested the Mastery Lifestyle Intervention (MLI): 
a culturally-relevant, manualized psychosocial group intervention 
that integrates evidence-based behavioral therapies – Acceptance 
and Commitment Therapy (ACT), Problem-Solving Therapy 
(PST) and Mindfulness. The MLI is a 6-week program designed to 
be integrated into regular prenatal care to facilitate more 
comprehensive care delivered by a nurse practitioner (NP) or 
certified nurse midwife (CNM). We propose the following 
hypotheses for a randomized controlled trial: Hypothesis 1a: 
Participants in the 6-week MLI will have decreased depressive 
symptoms, anxiety, stress, disengaged coping, and increased active 
coping compared to UC (our control group receiving only standard 
prenatal care) at end-of-treatment and after 6 weeks.  Hypothesis 
1b: The effects of MLI versus UC on depression, anxiety, stress, 
acculturative stress, and coping will be mediated via psychological 
flexibility and moderated by acculturation. Hypothesis 2a: 
Compared to UC, MLI participants will have significantly lower 
mean levels of CRH (Corticotropin Releasing Hormone) over time 
from baseline to end-of-treatment.  Hypothesis 2b: Compared to 
UC, MLI participants will have significantly higher progesterone 
levels and lower estriol levels (higher progesterone/estriol ratios) 
over time from baseline to end-of-treatment. Hypothesis 3: As 
compared to UC, infants from mothers in the MLI group will have 
longer gestational age, greater birth weight, and fewer NICU 
admissions. 

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Objectives: 
 
Primary Aim 1: Determine the efficacy of the MLI in pregnant 
minority women to decrease depressive symptoms, anxiety, 
perceived and acculturative stress, and to improve coping, versus 
usual care (UC), from baseline (14-20 weeks' gestation) to end-of-
treatment (20-26 weeks' gestation) and at a 6-week follow-up (26-
32 weeks' gestation), with acculturation as a moderator and 
psychological flexibility as a mediator. Exploratory Aim 2: 
Explore the effect of the MLI on neuroendocrine risk factors of 
preterm birth (PTB) (CRH, progesterone, and estriol) versus UC 
from baseline to end-of treatment. Exploratory Aim 3: Explore 
the effect of the MLI on infant birth outcomes (gestational age, 
birthweight, NICU admission in comparison to birth outcomes in 
the UC.  
Endpoints: 
The primary endpoints are depressive symptoms, anxiety, 
perceived and acculturative stress, and coping at 20-26 weeks and 
32-36 weeks' gestation of pregnancy, and the secondary endpoints 
are blood levels of CRH, progesterone and estriol as well as infant 
outcomes at delivery. 
Study Population: 
The populations of interest are Latinas and African American 
pregnant women living in the Houston metropolitan area. Our 
target sample is 238 pregnant women; allowing for a 20% attrition 
rate. Ages of pregnant women will be between 18 and 45 years; 
participants will need to identify as Hispanic or as African 
American. They will need to be in good health without systemic 
infections. The geographic area is the greater Houston area 
including outlying areas the Texas Medical Center (TMC) serves.  
Phase or Stage: 
This is a phase 2 study 
  
Description  
of Sites/Facilities  
Enrolling Participants: 
Participants will be enrolled from various obstetricians throughout 
the greater Houston area.  

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Description 
of 
Study 
Intervention/Experimental 
Manipulation: 
We will hold six weekly sessions of the study intervention (the 
Mastery Lifestyle Intervention, MLI) starting at 14-20 weeks' 
gestation to 20-26 weeks' gestation with each session lasting ~1-
1½ hours. We will give participants in the MLI group a participant 
handbook in either English or Spanish that has space for reflection 
and activities to complete at home. We have refined our facilitator 
handbooks extensively. Conducting the MLI with groups is 
feasible, acceptable, and advantageous as it is a) cost-effective, b) 
allows for group support and building a social network and c) 
encourages good role modeling. A recent meta-analysis found no 
significant differences in effectiveness in individual versus group 
formats for Cognitive Behavioral Therapy (CBT). We also have 
been using a web-based format over Zoom for groups. 
Study Duration: 
The study should take 52 months from first enrollment to 
completion of data collection. 
Participant Duration: 
Each individual participant will take 12 weeks for complete 
maternal data collection. Data about infants born to participants 
will be collected via chart review from delivery hospitals. 
1.2 
SCHEMA (SEE NEXT PAGE) 

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1.3 
SCHEDULE OF ACTIVITIES  
 
 
 

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2 
 
INTRODUCTION 
Background and Significance for Clinical Trial 
Psychosocial distress (depression, anxiety, chronic stress, acculturative stress) is prevalent in 
pregnant Hispanics (hereafter referred to as Latinas) and is associated with preterm birth 
(PTB) and low birth weight (LBW). PTB in 2017 for all births rose (9.93%), rising in Latinas to 
9.61% (1). Depressive symptoms, anxiety, perceived, and acculturative stress, and deleterious 
coping are important risk factors related to these results. About 10-25% of pregnant women in the 
U.S. have depressive symptoms, with resulting negative sequelae for women, children, and 
families (2). Antenatal depression, a strong risk factor for postpartum depression, highlights the 
need to intervene early during pregnancy (3). Although postpartum depression is outside the scope 
of study, we will examine it in future studies, and we will examine the effect of untreated antenatal 
depression on infant outcomes at birth (LBW, PTB). A meta-analysis found that pregnant women 
with untreated depression had an odds ratio of 1.56 (1.25-1.94) for PTB and 1.96 (1.24-3.10) for 
LBW (2). Most evidence indicates that there are ethnic disparities in antenatal depression; Latinas 
have higher risk factors for depression as compared to non-Hispanic white women (2), with rates 
of depression as high as 35-40%. In our previous study with Latinas (Ruiz-R01NR07891), 30% 
had antenatal depression. The prevalence of depression and accompanying psychosocial distress, 
particularly among impoverished women, is a significant public health problem. Anxiety 
commonly co-occurs with depression. As many as 60% of women diagnosed with depression also 
met diagnostic criteria for anxiety (5). Similarly, perceived stress is another well-established risk 
factor for antenatal depression (6) that affects PTB (7-10). Of concern, studies of antenatal 
depression in Latinas failed to account for acculturation, the multidimensional process of 
psychological and cultural change that occurs when a person interacts with two or more cultures 
(11). Previous results for ours and other’s studies indicate that greater acculturation results in 
worsened mental health (12, 13); it is important to consider acculturation as a moderating risk 
factor for Latinas. Acculturative stress, the stress associated with acculturation, also relates to 
anxiety and depression. We will examine acculturation and acculturative stress as part of the social 
risks for poor mental health and birth outcomes. We will avoid methodological weaknesses by 
focusing on Latinas of Mexican origin, avoiding heterogeneity (14). We will not ascertain if a 
participant has a social security number, as doing so was noted as a human subject concern by 
reviewers.   
Psychosocial distress is also very prevalent in pregnant African American (Black) women. A 
diagnosis of depression, anxiety and stress during pregnancy worsens the risk for PTB and LBW, 
particularly in Black women. Racial and ethnic differences in preterm birth rates continue. In 2020, 
the rate of preterm birth among African American women (14.4%) was about 50 percent higher 
than the rate of preterm birth among white women (9.1%)) (CDC website, 2021). These stark 
numbers nationally indicate a need for better preventive interventions. Data also indicates 

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disparities in the use of mental health services for both Black and Latina women (Ponting et al., 
2020). In a systematic review (Ponting), the rates for both Black and Latina women to use mental 
health services during pregnancy are between 4 and 5%, and they are less likely to receive follow 
up for treatment (Goodman & Tyer-Viola, 2010). Barriers are infrequent screening, particularly in 
clinics attended by a lot of Latinas and Blacks, as well as healthcare mistrust (Levy & O’Hara 
2010). The most common treatment for psychosocial distress has been cognitive behavioral 
therapy (CBT) (Ponting, 2020). Most randomized controlled trials (RCTs) do not measure anxiety 
as an outcome, that is vitally needed. Additionally, cultural adaptations with CBT programs can 
improve clinical outcomes in ethnic minorities (such as coping with discrimination). 
Psychosocial factors increase the risk of adverse birth outcomes.  
   Depressive Symptoms and Anxiety. Evidence from several meta-analyses (16-18) indicates that 
the use of antidepressant medications (particularly Selective Serotonin Reuptake Inhibitors 
[SSRIs]) is possibly related to increased risk of PTB as well as LBW. These findings underscore 
the need to weigh the effect of untreated depression against the potential effects of antidepressant 
exposure, (18) and to identify and implement effective nonpharmacological treatments. Treating 
depression during pregnancy for low-income women can be difficult due to limited insurance 
coverage for mental health and out of pocket costs, (19) as well as the stigma associated with 
mental health visits. Depression is often comorbid with anxiety; together, they increase the risk for 
PTB (20). Several researchers have found strong links between anxiety and PTB (21). There is 
also evidence that maternal prenatal anxiety programs the fetus resulting in emotional and 
behavioral problems for the child (21-23). Based on the evidence related to risk, we will target 
depression and anxiety to reduce psychosocial risk, ultimately reducing the risk of adverse birth 
outcomes.  
   Chronic Stress. Perceived stress has been extensively studied in relationship to PTB, with strong 
empirical evidence indicating links between prenatal stress and PTB (7,8). However, acculturative 
stress and perceived stress together have the greatest impact on elevated depressive symptoms in 
Latinas (24). 
   Acculturative Stress refers to stress responses by immigrants culturally adjusting to a new society 
as they are challenged by an unknown culture and differing social norms. Acculturation involves 
embracing new behaviors and customs while either preserving or losing those of the traditional 
culture. Often acculturation and acculturation stress result in intergenerational family conflict, 
maladjustment, and marginalization (25, 26). Most recently, acculturative stress for Latinas may 
be exacerbated given the recent increase in sociopolitical stressors (e.g., anti-immigrant, anti-
Hispanic policies, hate crimes). Although evidence on the health effects of anti-immigration 
rhetoric and policies is still being collected currently, studies have related sociopolitical stress (i.e., 
anxiety about deportation, awareness of anti-immigration policies) with poorer mental health (27) 
as well as higher systolic blood pressure and pulse pressure among Latina adults, known risk 
factors for PTB (28). Documented increases in heightened profiling and deportation may not only 

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result in increased acculturative stress but also decreased healthcare use (27). For instance, in a 
study using birth certificate data, severe sociopolitical stressors among Latinas indicated a 
detrimental impact on PTB (29). This study illustrated the implications of racial stressors for 
increased PTB in both the health of Latina immigrants as well as U.S. born Latinas. Rates of LBW 
and PTB also increased in Latina mothers in Iowa after a surprise immigration raid (30). Further, 
LBW risks in this study were worse for mothers with low education, who had fewer coping 
resources. Investigators speculated that the pregnant Latinas’ neuroendocrine balance and coping 
resources were affected after the raid, leaving their infants vulnerable to a dysregulated endocrine 
environment. Previous scientists found acculturative stress to be a major contributor to poor health 
outcomes (31,32), but more work is needed to understand the role of maternal mental health. Our 
last major study with Latinas (Ruiz-R01NR07891) found acculturative stress (as measured by the 
Acculturative Stress Scale) (33) to be significantly associated with depression (r = .21, p < .000) 
and chronic stress (r = .24, p <.000), as measured by the Perceived Stress Scale (34). Both types 
of stress are proposed targets to reduce psychosocial risk.  
   Coping. Poor coping skills, such as disengaged coping, may also be associated with 
compromised mental health and risk of poor birth outcomes. Disengaged coping may be 
conceptually defined as avoidance, behavioral disengagement, or self-blame. Relations between 
coping and antenatal depression among Latinas remain minimally explored; however, among 
Latinos in general, Torres found among 148 adults, poor coping was associated with worsened 
depression (35). Of further concern, Borders, studying 294 welfare recipients, found poor coping 
skills (avoidant or disengaged coping) were associated with LBW babies (36). In general, pregnant 
women with coping behaviors of avoidance or distancing (i.e., behavioral disengagement) have 
had more PTB and postpartum depression (36-39). Alternatively, active coping may be 
conceptually defined as the use of emotional and instrumental support, use of humor, and/or 
acceptance (vs. avoidance) of internal distress (40). Ours and other’s evidence indicate that first-
generation Latinas used less active coping skills than acculturated Latinas (41,42). We will focus 
on increasing acceptance of difficult internal states (i.e., depression, anxiety) and the use of more 
action-oriented (vs. avoidant coping) to reduce psychosocial risks both of Latinas and Black 
women.   
Neuroendocrine factors are important for the maternal-fetal response to psychological 
distress. Research has demonstrated that neuroendocrine pathways mediate the effects of 
psychosocial factors on health outcomes, i.e., particularly fetal development and infant birth 
outcomes (43). In seminal work, Chrousos (44) linked the neuroendocrine system to the stress 
response and health outcomes. The hypothalamic-pituitary-adrenal (HPA) axis (in pregnancy, the 
placental-pituitary-adrenal-axis) is one of the major systems involved with the stress response. The 
main agent of this axis is Corticotropin Releasing Hormone (CRH); placental CRH is identical to 
hypothalamic CRH both biologically and in its response to stress (45). Wadhwa (46,47) states that 
the placenta has the ability to receive, process, and respond to certain stimuli, and thus may take 

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on functions similar to the central nervous system in the stress response. Placental CRH facilitates 
the placenta getting information to the fetus. Increases of CRH early in pregnancy have predicted 
the onset of preterm labor in ours and other’s results (48-52). The chronicity of stress is particularly 
important in relation to the initiation of early labor (53). Estrogen and progesterone are other 
important endocrine factors linked to CRH and related to labor. Increases in estrogen (estriol, E3) 
and decreases in progesterone shift the endocrine balance. Placental CRH stimulates E3 induced 
changes in the cervix and uterus, part of the initiation of labor (54). It is important to explore the 
effects of an intervention to reduce psychosocial distress on some of the key pathways, such as 
CRH, progesterone, and estriol. In our previous study with Latinas (55), the combination of 
acculturation, depressive symptoms, progesterone, and E3 predicted PTB, indicating that the 
combined impact of these factors produced the greatest risk. We propose to a) test a behavioral 
intervention to reduce psychosocial risks, and b) explore the impact on neuroendocrine factors 
and infant birth outcomes.  
Cognitive behavioral therapy (CBT) is recommended for reducing antenatal depression, yet 
effects are small, and few studies have targeted PTB or Latinas. In recent evidence, a report of 
interventions to prevent perinatal depression by the U.S. Preventive Task Force (USPSTF) (56), 
counseling interventions, primarily CBT, were recommended to prevent perinatal depression. 
Fifteen of the 20 trials reviewed had counseling interventions that were focused on women who 
were known to be at risk for perinatal depression, particularly depression history or symptoms. 
Analysis of counseling interventions revealed a pooled standardized effect size of 0.2, considered 
a small effect (57), which suggests new therapies are needed to obtain larger effects.  
   Moreover, the only study to examine the effect of therapy on PTB was an RCT conducted in 
Spain and France to evaluate the Tourne approach versus usual care to reduce depressive 
symptoms (58). The Tourne approach used humanistic and cognitive techniques during 10 
antenatal group sessions for both the woman and her partner. Nurse midwives were facilitators. 
Depressive symptoms were not significantly reduced; however, there were major differences in 
the infant outcomes. In the intervention group there were only 3 PTBs (4.4%) with higher 
birthweights (p =.01), compared to 13 PTBs in the control group (22.4%) (p = 0.003). Infant 
outcomes were much improved in women who received behavioral therapy, suggesting the need 
for trials evaluating both proximal psychosocial risk factors and infant outcomes, such as we are 
proposing.  
   CBT has primarily been used with women who are Caucasian, married and middle class, and not 
well tested in Latinas; we found only a few RCTs using CBT targeting depression in pregnancy 
that included Latina women (59-61). These studies did not specifically address the unique 
situations associated with Latinas and their distinctive risk factors. Jesse (59) et al. focused on 
perinatal depression and used traditional CBT integrated into prenatal care, for rural low-income 
minority women, both Latinas and Black women. They could not recruit enough Latinas, so the 
feasibility of this intervention with Spanish speaking Latinas is still unknown. This RCT was more 

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effective for low to moderate risk depressive symptoms on the Edinburgh Postnatal Depression 
Scale (EPDS) and was particularly effective for Black women. This study provides evidence of 
the effectiveness of CBT for especially Black pregnant women. Munoz (60) focused on Latinas 
and limited the sample to women with major depression. The 12-week program used social 
learning concepts, attachment theory, and reality management. It was ineffective in several areas: 
a) the women completed only 7 of the 12 sessions on average, and importantly, b) the depression 
scores were not changed after the intervention. Le (61) recruited Central American Hispanics, who, 
as new immigrants (4 years or less in America), had a low risk for depression. A study limitation 
was the lack of consideration for psychosocial risks related to acculturation. Another study focused 
on using CBT with pregnant Black women in Washington, DC. focusing on several risk factors, 
not just psychosocial ones. This study reported results indicating it was possible to combine such 
an intervention for Black women integrated into prenatal care. In sum, studies applying CBT with 
Latinas did highlight that behavioral therapy can be integrated into the prenatal setting to serve 
this population. Our proposed intervention is based on the third wave (newest) generation of CBTs 
not tested in any studies reviewed in the USPSTF analysis, thus filling a gap and advancing science 
by testing the newest CBT methods. The three studies using traditional CBT with Latinas focused 
exclusively on depression, indicating a need for a broader transdiagnostic intervention for other 
psychosocial distress.   
Acceptance and Commitment Therapy (ACT) (62), a third-wave Cognitive Behavioral 
Therapy, has a strong evidence-base for effects on depression and anxiety, with burgeoning 
support for women in the perinatal period. Although it is a CBT, ACT is an innovative 
behavioral treatment that represents a significant shift in philosophy and perspective. A primary 
tenet of ACT involves the notion that avoidance or attempts to exert strong control of negative 
emotions, thoughts, or bodily sensations results in and perpetuates psychopathology (e.g., 
depression, anxiety) (63-65). ACT methods endorse an acceptance rather than a control-based 
model to promote more flexible and adaptive behavior consistent with client-identified, personal 
values. ACT has been applied to a myriad of problem areas (e.g., substance abuse, chronic pain) 
and has a particularly strong evidence base in depression with moderate evidence for anxiety (66, 
67). Most studies with pregnant women tend to focus narrowly on perinatal depression, yet ours 
and other’s work (9, 46, 68, 69) suggest a high prevalence of anxiety and stress as well. 
Interventions are sorely needed to address co-occurring mental health needs among perinatal 
women (e.g., stress, depression, anxiety, coping), and therefore a “transdiagnostic” approach, 
such as ACT, is ideal (67).  
ACT has benefit over other similar treatments in that it links to a theoretical framework with a 
corresponding comprehensive set of behavioral change principles. Psychological processes 
involved in psychopathology and target mechanisms for change are identified. Primary processes 
include acceptance (as opposed to avoidance), values identification, committed action, 
mindfulness, and cognitive defusion, only a few of which may be targeted with currently 

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recommended CBTs, including interpersonal therapy (IPT). Psychological flexibility is the 
overarching process comprising the six primary, individual processes, and has been associated 
with most forms of psychopathology and related problems (70). Stotts (co-I), Villarreal (co-I), 
Suchting (co-I), and Northrup (co-I) (71) conducted a longitudinal secondary analysis that found 
psychological flexibility to be a mediator of early (1-2 weeks postpartum) and later (6 months 
postpartum) depressive symptoms among new mothers of NICU infants. Depressive symptoms in 
women low in psychological flexibility persisted or increased by 6 months postpartum relative to 
women who were more psychologically flexible. Many studies support ACT processes as 
mechanisms of change and potential targets of treatment. In fact, among ACT studies investigating 
mediators of treatment, about 50% of the between-group differences in follow-up outcomes can 
be accounted for by differential levels of psychological flexibility (72). Due to its emphasis on 
psychological flexibility, we believe ACT is well suited to reduce stress among Latinas as they 
adapt to the American culture, as well as African American women with the challenges they face 
related to discrimination. Other CBT treatments have identified very few mechanisms of change 
for psychosocial distress in perinatal women. The proposed study will fill this gap.   
Problem Solving Therapy (PST) (73) may target stressful external problems experienced by 
both pregnant Latinas and Black women as it teaches tangible problem-solving skills. PST, 
a behavioral intervention developed from traditional CBT, has been found effective in treating 
depression (73-76) and anxiety (77,78) Unlike IPT (79) and significant to the proposed study, PST 
has been better adapted for use within primary and other health care settings and can be 
administered by physicians and NPs (80). Further, PST has demonstrated effects on mental health 
outcomes when delivered either individually or in group settings. PST treatment focuses on 
helping individuals solve multilevel stressors and concrete problems. We contend that a combined 
treatment of ACT and PST is a much-needed intervention to reduce maternal psychosocial risks 
for vulnerable Latinas and African Americans, thus improving clinical practice. 
2.1 
STUDY RATIONALE AND BACKGROUND 
Pregnant Hispanic women hereafter referred to as Latinas, are at increasing risk for psychological 
distress which leads to adverse birth outcomes such as preterm birth (PTB, gestational age < 37 
weeks) and low birthweight (LBW, <2500 grams) (81,82). African Americans are also at 
considerable risk for poor pregnancy outcomes, of even greater concern than Latinas are. The 
cause of PTB is multifactorial (83, 84), with many of the risk factors difficult to modify (85). 
Extensive research has been focused on preventing PTB in the United States (US) (86), 
predominantly testing medical interventions such as drugs (17-alpha hydroxyprogesterone 
caproate) or cervical cerclage; with minimal focus on decreasing psychosocial risks.  Women 
reporting “high” levels of psychological stress are at 25-60% increased risk for PTB compared to 
those with “low” stress (46). The American College of Obstetrics and Gynecology has endorsed 
psychosocial screening at least once each trimester in pregnancy (87). Acculturative stress and 

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perceived stress together are known to elevate depressive symptoms in Latinas (88, 89), 
particularly Latinas who have assimilated into U.S. culture, and are associated with PTB (68, 90-
93). Despite this, many care providers do not recognize or diagnose depression during pregnancy; 
and even if depressed women are identified, few are treated (94). This is a significant unmet need 
for both Latinas and Blacks (95), leaving them at increased risk of both PTB and postpartum 
depression (92) which has devastating and long-term effects for mother and child (93). Our prior 
research, using a psychoneuroimmunology (PNI) framework, has identified psychological risk 
factors (depressive symptoms, anxiety, stress, acculturative stress, coping) and neuroendocrine 
risk factors (high Corticotropin Releasing Hormone [CRH], lower progesterone, higher estriol) at 
22-24 weeks gestation as strong predictors of PTB in Latina women. The rate of prematurity was 
unacceptably high in this understudied population of Latina women (as high as ~16% in our 
previous study) (97). New interventions targeting additional risk factors need to be identified 
and rigorously tested for two of the at-risk minorities (85).  
To address the gaps related to interventions for Latinas and Black women, we have developed, and 
pilot tested the novel Mastery Lifestyle Intervention (MLI): a culturally-relevant, manualized 
psychosocial group intervention that integrates two evidence-based cognitive behavioral therapies 
(CBT) – Acceptance and Commitment Therapy (ACT) and Problem-Solving Therapy (PST).  Our 
study is unique in that we propose to target psychological risk factors with the MLI and also assess 
the impact on associated neuroendocrine risk factors, based on our evidence (97,98) as well as 
extensive empirical evidence in other populations (7, -9, 99). This innovative combination of two 
interventions during pregnancy is expected to have an effect on clinical outcomes as well. The 
MLI is a 6-week program designed to be integrated into regular prenatal care to facilitate more 
comprehensive care delivered by a nurse practitioner (NP) or certified nurse midwife (CNM). We 
have specifically targeted the timing of the MLI prior to maternal biological changes seen at 22-
24 weeks gestation in our previous work. Our pilot study of the MLI demonstrated feasibility, 
acceptability and a moderate to large pre-post effect size for reducing anxiety, and a moderate 
effect size in reducing depressive symptoms. We are now poised to test the MLI in a rigorous RCT 
conducted in early pregnancy and integrated into a prenatal care setting for Latinas and African 
Americans. To our knowledge, this will be the first study to a) explore both the psychosocial and 
biological effects of ACT and PST and, b) explore the effects of ACT and PST related to improving 
gestational age, birthweight and NICU admission. We propose the following aims: 
Primary Aim 1: Determine the efficacy of the MLI in pregnant Latina and Black women to 
decrease depressive symptoms, anxiety, perceived and acculturative stress, and to improve coping, 
with psychological flexibility as a mediating factor and acculturation as a moderator, versus usual 
care (UC), from baseline (14-20 weeks' gestation) to end-of-treatment (20-26 weeks' gestation) 
and at a 6-week follow-up (32-26 weeks' gestation). Hypothesis 1: Participants in the 6-week MLI 
will have decreased depressive symptoms, anxiety, stress, disengaged coping and increased active 
coping compared to UC at end-of-treatment and at a 6-week follow-up. Exploratory Aim 2: 

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Explore the effect of the MLI, versus UC, on neuroendocrine risk factors of PTB (CRH, 
progesterone, and estriol) from baseline to end-of treatment.  Hypothesis 2a: Compared to UC, 
MLI participants will have significantly lower mean levels of CRH over time from baseline to end-
of treatment.  Hypothesis 2b: Compared to UC, MLI participants will have significantly higher 
progesterone levels and lower estriol levels (higher progesterone/estriol ratios) over time from 
baseline to end-of treatment.  Exploratory Aim 3: Explore the effect of the MLI on infant birth 
outcomes (gestational age, birthweight, NICU admission). Hypothesis 3: As compared to UC, 
infants from mothers in the MLI group will have longer gestational age, greater birthweight, and 
less NICU admissions. 
Impact: We expect the MLI will provide a greatly needed, novel, feasible, and effective 
nonpharmacological program added to the toolbox of treatments assisting providers to improve 
health during pregnancy. This work is consistent with the mission of NICHD to improve prenatal 
health, particularly in relationship to health disparities. It is an important step in identifying new 
pregnancy interventions to possibly reduce the risk of PTB. 
 
Background  
Conceptual Framework. We have based our previous work for the last 20 years on the 
psychoneuroimmunology (PNI) model. This model (Figure 1) of “psycho,” or psychological 
factors (such as depressive symptoms, anxiety, etc.), with neuroendocrine factors (such as 
hormones and corticosteroids), with immunological factors (inflammatory markers, infections) 
predicts health outcomes. From this framework, we have tested depressive symptoms, anxiety, 
stress, and coping as psychological factors impacting birth outcomes in Latina pregnant women. 
Our evidence, as well as extensive evidence from the literature, indicates the importance of testing 
a model to reduce psychobiological risk and, subsequently, poor infant outcomes (100-104).  
 
 

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Figure 1 
PNI model 
Moderating 

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Observational Results. In 
our last study, PI-Ruiz-
R01NR07891, we had a 
sample of 515 pregnant 
Latinas. We conducted an 
observational study at 22-24 
weeks 
gestation 
and 
measured 
acculturation, 
progesterone, 
cortisol, 
cotinine, age, marital status, 
income, stress, depressive 
symptoms, 
and 
coping. 
These risk factors were 
tested as predictors of a 
higher-order latent factor, 
that 
we 
named 
the 
Cumulative 
Risk 
Profile 
(98). We hypothesized that 
the cumulative effect of 
biological, 
cultural, 
socioeconomic, 
and 
psychological risk factors 
would 
predict 
neonatal 
health, represented through 
a latent outcomes construct. 
We sought to evaluate the strength of the factors that put these women at risk for poor outcomes 
by a predictive structural equation model. Consistent with our hypotheses, poor birth outcomes 
were predicted by risk factors at multiple levels of analysis, including biological, cultural, 
socioeconomic, and psychological. The tested empirical model of a Cumulative Risk Profile 
predicting poor birth outcomes (lower birth weight, decreased gestational age, more NICU 
admissions) had a good model fit and was scientifically rigorous (See Figure 2). Young, low 
income, single (socioeconomic factor), and greater acculturation (cultural factor) have the highest 
regression coefficients predicting the risk of having a poor pregnancy outcome. Stress and 
depressive symptoms were also important psychological factors predicting risk and are modifiable, 
unlike most other risk factors. Coping, particularly negative coping as noted from the different 
subscales in this figure, predicted an increase in depressive symptoms and stress, suggesting 
another treatment target. These results not only demonstrate our ability to conduct large studies 
but also provide the rationale to target modifiable psychological risk factors to prevent PTB. We 
Figure 2 Cumulative Risk Profile 
SEM Results 

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posit that many of the same risks may be modifiable also in the Black population. The MLI is a 
targeted intervention to reduce stress and depressive symptoms and to increase adaptive coping.   
We also have results using latent profile analysis to identify characteristics of low-, moderate-, and 
high-risk groups for PTB (97). The low-risk group (n = 157) had 7.7% PTBs (n = 12). 
Characteristics of women in the low-risk group: slightly older (mean = 25), married (56%), the 
least acculturated (more Spanish speakers, fewer years in the U.S., more identification with 
Mexican cultural identity) as compared to the other two groups. The low-risk group had very low 
depression scores on the BDI (mean = 6). The moderate-risk group for PTB (n = 272) had 12% (n 
= 32) PTBs. Characteristics of the moderate-risk group: average childbearing age (mean = 24), 
slightly fewer married women than the low-risk group (48%), more acculturated (greater English 
speakers, more years in the U.S., mean between second and third generation) as compared to the 
low-risk group. Depression scores were low (mean = 9 on the BDI), and coping was more active 
vs. avoidant. The high-risk group had the least married women; n = 21), the most acculturated 
(more English proficiency, the least Spanish proficiency, and the longest time in the U.S.) as 
compared to the moderate- or low-risk group. They had high scores on the BDI (mean of 22 or 
moderate depression). They also had the highest scores on disengaged coping and lowest scores 
on active coping. These results indicate an association between psychological symptoms and PTB 
and the need to target coping and lowest scores on active coping. These results indicate an 
association between psychological symptoms and PTB and the need to target psychological 
factors, particularly disengaged, avoidant coping, with pregnant Latinas. (86)  
 
Development of the Mastery Lifestyle Intervention (the MLI): Rationale and Justification. The 
MLI is a manualized psychosocial group treatment that integrates two evidence-based 
interventions – Acceptance and Commitment Therapy (ACT) and Problem-Solving Therapy 
(PST). ACT is a contextual behavioral treatment systematically applied and investigated in diverse 
settings, with diverse populations and cultural backgrounds, and for a variety of behavioral health 
problems (62,105,106-108). ACT can easily be done in group formats and has reduced depression 
in various populations. For example, in a recent study (108), stroke survivors who received group-
based ACT for 4 weekly 2-hour didactic sessions, as compared to a treatment-as-usual group, had 
significantly reduced depression and increased hopefulness with medium effect sizes. ACT helps 
increase psychological flexibility, identify personal values, and implement behavioral changes that 
are personally meaningful to the individual (i.e., committed action). Kashdan and Rotterburg (109) 
define psychological flexibility as “the measure of how a person: (1) adapts to fluctuating 
situational demands, (2) reconfigures mental resources, (3) shifts perspective, and (4) balances 
competing desires, needs, and life domains.” This concept addresses much of what Latina women 
are required to do in pregnancy and as they acculturate. This concept that also pertains to many 
challenges Black women face in daily life. PST is a behavioral treatment that teaches recognition 
of how one orients to a problem and focuses on the development of specific problem-solving 

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skills. It is flexible in its application and works well as part of a larger, integrated treatment 
package for different populations. PST provides training about how to better resolve and cope 
with stressful life problems (75) has been used as a stand-alone treatment, and has been 
effective in pregnancy (110, 111). PST promises to also provide an effective treatment for 
Black women to cope with some of their difficult problems. We therefore believe that the 
MLI may easily work well with both Latinas as well as African Americans, as the participants 
identify their own values and problems and determine the way best way to problem solve 
considering their own situation. 
We have integrated ACT and PST in the MLI to complement and build on each other. ACT 
enhances flexibility in responses to internal stimuli (thoughts, feelings, physical sensations), while 
PST teaches more concrete problem-solving skills in the external environment. Both assist women 
in pursuing valued goals. PST is a natural extension of the ACT process of committed action. ACT 
and PST both teach effective coping strategies related to changes and roles Latinas may face due 
to pregnancy as well as acculturation, and difficulties related to discrimination in Black women. 
The MLI facilitator manual and the participant handbook have been translated into Spanish. 
 
 
D.2.c. Pilot Study Results of the Mastery Lifestyle Intervention (MLI) (112) with Latina women. 
Feasibility. We conducted a one arm, 
pre-post test pilot study that included 
3 cohorts with 15 participants. All 
but one of 15 participants attended 
100% of the sessions. Several 
attempts at recruitment were initiated 
(e.g., recruitment with a research 
assistant not part of the obstetrics 
practice), however most efficacious 
was contracting a medical assistant 
from the obstetrics practice to recruit 
pregnant women at the care site and 
holding the sessions in the lobby of 
their provider, resulting in better 
recruitment and attendance rate for 
the 
sessions. 
The 
pilot 
trial 
elucidated 
that 
the 
recruitment 
window needed to be 14-20 weeks 
gestation to maximize the number of 
participants. Six sessions were well tolerated and attended, and we will continue that number for 
the proposed RCT. The use of electronic tablets was highly feasible; the use of the tablets by 
Figure 3. Evaluation 
Data Pilot 

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participants worked well.  
Acceptability. Figure 3 above provides evaluation data from the MLI pilot participants. Women 
ranked the answers on a survey on a scale of 1-7, with 7 being excellent and 1 being very poor. 
Participants reported that 6 sessions from 1.5 to 2 hours appeared to be ideal. From these results, 
we have added more group engagement.  
Pretest and Posttest Results. From pre- to post-assessment, the intervention reduced anxiety and 
depression and negative coping (effect sizes ranged from -.30 to -1.5 for anxiety and -0.45 to -0.58 
for depression). Positive coping (e.g., use of emotional or instrumental support, use of humor; 
acceptance) was increased as well, with subscale effect sizes ranging from 0.2 to 0.39. Negative 
coping (e.g., avoidance and distraction) was decreased with subscale effect sizes ranging from -
0.28 to -0.61. Our pilot results were positive and support proceeding to a larger RCT to 
further establish efficacy for the MLI. 
2.2 
RISK/BENEFIT ASSESSMENT  
2.2.1 KNOWN POTENTIAL RISKS  
 
What are the risks of taking part in this study? 
For the MLI (or intervention) group:  
• There is a risk that the MLI may not be as good as traditional therapy for anxiety, 
depression or stress.  
• There is also a risk that a participant can have some emotional discomfort from taking part 
in the MLI group. Due to the nature of the MLI group sessions, there may be sensitive 
emotions or problems revealed. To decrease this risk, if needed, the study team will have 
a list of resources we can give to the participants should they experience discomfort.  
• At the first group session, we will discuss the rules of the group session in order to minimize 
the risk of participation and maintain confidentiality. **  
**Exceptions to the confidentiality rule include: 1) if child or elder abuse is revealed, the session 
leaders are required by law to report that to child or adult protective services; and, 2) if a participant 
indicates suicidal or homicidal thoughts (group leaders may disclose this information to protect 
the participants or others [in accordance with Texas law]). 
 
Discomforts for either group associated with this research include: 
• There is a minimal risk of mild pain or discomfort, bruising and swelling from the blood draw 
at the puncture site, or there may be dizziness or fainting.  There is a small risk of infection. 
We will apply pressure with a sterile gauze dressing for several minutes to avoid bruising and 
infection and assist anyone if they are faint. 
• A participant may get tired or bored when they are filling out the questionnaires. The study 

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team will make sure the participant does not have answer any question they do not want to 
answer.  
• A participant may have mild emotional discomfort from answering the surveys. 
• With research participation, there is a small risk of a loss of confidentiality. Research personnel 
will work hard to maintain participant confidentiality (privacy).  We will do our best to 
maintain participant privacy throughout the time in the study. 
 
2.2.2 KNOWN POTENTIAL BENEFITS   
What are the potential benefits to taking part in this study?  
• The MLI group will be facilitated by a nurse practitioner/licensed advanced practice nurse, 
who will be able to address anxieties or problems related to pregnancy and mental health 
• Improved emotional health 
• Improved coping 
• Decreased stress 
• Decreased depression and anxiety symptoms  
• Improved relationships with the partner of the participant and/or people close to participant 
• Improved sleep  
• Benefit to other pregnant women in the future  
• Lowered risk for preterm births as a result of improved emotional health in the MLI group  
 
2.2.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS   
Protections against Risk: There should be minimal risks from participating in the research study. 
The risks to the participants related to the effects of untreated depression and anxiety on the fetus 
are much greater than any of the risks delineated in participating in the study. A physical risk is 
that of bruising and /or pain from the venipuncture site. Pressure will be applied with a sterile 
gauze dressing for several minutes to avoid bruising. Study personnel will also make sure they use 
aseptic techniques to clean the skin before venipuncture, as well as ensuring the use of sterile 
needles. Women may have some emotional distress from answering the questionnaires. There is 
some risk for the participants to travel to the sites either by bus or by car, but this risk is no greater 
than they have for everyday activities that they travel to or risk to come to their prenatal 
appointment. In addition, the fact the sessions are facilitated by a certified NP/CNM gives an added 
benefit as she should be able to handle medical concerns that may arise. The group sessions will 
be conducted either on-site in the MLI office or via Zoom. The group sessions will be planned for 
maximum privacy if conducted in person. 
 
 

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To minimize any potential risks, we will use the following protocols: 
Handling of Depression or Suicidality: Depression questionnaires will be completed at 14-20 
weeks' gestation, at 21-27 weeks' gestation, and at 32-36 weeks' gestation for participants in either 
group. The Clinical Team Member (CTMB) will review the baseline score for the CES-D 
immediately on-site after the participant completes it and is received by CTMB. We will consider: 
• If the score is > 36 i.e., 36 or above, we will administer the Columbia- Suicide Severity Rating 
Scale (C-SSRS) and follow protocol for scoring (see attached protocol) 
• The CTMB will also advise the prenatal care provider if the score on the CES-D is > 36 so that 
they may make an immediate referral for treatment of severe depression. 
• The CTMB will also complete an “Adverse Score Follow-up Care Report” to indicate the 
score, action taken, and any additional notes that might become important should reporting to 
the IRB become necessary. In the MLI group, the NP/CNM facilitator will monitor depression 
and suicidality while conducting the group therapy. In the UC group, the prenatal care provider 
will monitor women as is customary in their practice and follow the previously established 
standard of care. 
 
Handling of Disclosure of Domestic Violence: Although not a focus of this study, it is possible 
that a woman would disclose interpersonal violence during or after a group session. Our initial 
curriculum packets contain resources and supports in the Houston community for women 
experiencing interpersonal violence. If domestic violence is revealed, the CTMB or NP/CNM will 
individually and discretely talk to the woman to see if she would like help developing a safety plan 
and will offer her a list of resources for domestic violence. The NP/CNM should have training 
from her academic classes and experience assessing for domestic violence from her professional 
practice. We will also include a refresher training during our team trainings for practitioners so 
that all team members know the current, active available resources for women experiencing 
interpersonal violence. We will encourage women to share their experiences with their prenatal 
care providers, and, if needed – will inform her care provider on her behalf and with her permission 
as noted on the Adverse Score Report Form. 
 
Emotional Upset During or After Completing Questionnaires: Some of the items on the 
questionnaires may cause emotional upset, particularly as items may cause a participant to consider 
how she is feeling. If she is not feeling well and is more aware of her feelings during or after 
completing the questionnaire, the NP/CNM will discreetly take her to a private area to reassure 
her and support her. The group sessions should also provide an opportunity for others to offer 
support.  The woman will be reminded that she can check in with her prenatal care provider, too. 
Although the risk for more severe emotional upset is possible, it is very unlikely and will be noted 
on our Adverse Score Report Form if it does occur. In our prior R01s using these questionnaires 
with 1000+ women this situation did not arise. 

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Biohazard Safety: Handling of Body Fluids and Universal Precautions: Only sterilized, 
disposable butterfly needles will be used for drawing blood. Participants will be instructed to let 
the CTMB know of any problems during the blood draw; however, procedures are such that the 
risks of problems occurring during blood draws are rare. Pressure will be applied at the 
venipuncture site to avoid bruising. The CTMB will monitor the participant for any problems after 
the blood draw. All persons handling blood or body fluids will employ strict universal precautions 
to avoid the spread of blood borne pathogens to themselves or others and use personal protective 
equipment. Blood will be transported in coolers by the CTMB that has had training in blood borne 
pathogens and universal precautions. There should be no legal risks in obtaining urine for cotinine 
checks since smoking is legal. 
 
Loss of Confidentiality: Due to the nature of group sessions there may be sensitive emotions or 
problems revealed by the participants. At the first group session, we will review the rules for the 
sessions. The first rule is that what is said in the group stays in the group so that people are not 
afraid to share and help each other. 
 
The only exception to this rule is if child abuse, elderly abuse, suicidal indications or homicidal 
thoughts are revealed. For child and elderly abuse, mandatory reporting will be done to child and 
elderly protective services by session leaders as required by law. For suicidal indications or 
homicidal thoughts session leaders may disclose information to prenatal providers in accordance 
with Texas law. 
 
Confidentiality of participants will be assiduously protected. No names of individuals will be 
shared or published at any time. Each participant will be assigned a unique code number. Only the 
NP/CNM, and CTMBs will have access to the master list of participant names and code numbers 
with contact information. However, the PI and other investigators will make every effort to not 
examine this list as they need to be blinded as to groups for analysis purposes. The master list will 
remain under a protected password for the CTMB or NP/CNM to use for follow-up. The CTMB 
who will be drawing the blood will know the participant names and numbers of the blood samples 
and urine samples to ensure proper labeling of the biological samples and the questionnaires. Study 
personnel will remain blinded as to results until the study is completed. Staff at the physician office 
will not have access to any individual’s questionnaire results, laboratory specimens, or data 
analysis results. 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS 
OF ACTION 
Primary 
 
 
 
To determine the efficacy 
of the MLI in pregnant 
minority women to 
decrease depressive 
symptoms, anxiety, 
perceived and acculturative 
stress, and to improve 
coping, with psychological 
flexibility as a mediating 
factor and acculturation as 
a moderating factor, versus 
usual care (UC), from 
baseline (14-20 weeks' 
gestation) to end-of-
treatment (20-26 weeks' 
gestation) and at a 6-week 
follow-up (32-36 weeks' 
gestation). This objective is 
to demonstrate efficacy.  
The primary 
endpoints are 
depressive 
symptoms, 
anxiety, 
perceived and 
acculturative 
stress, and coping 
at the end of a 
six-week 
treatment at 20-
26 weeks' 
gestation of 
pregnancy and at 
32-36 weeks' 
gestation to see if 
the MLI group 
has improved 
scores as 
compared to 
usual care.  
Primary antecedents are: 
depressive symptoms, 
anxiety, perceived and 
acculturative stress and 
coping. Psychological 
flexibility is a mediator and 
acculturation is a moderator 
for the antecedents.   
We propose that 
the primary 
endpoints affect 
the 
neuroendocrine 
response of 
Corticotropin 
Releasing 
Hormone 
(CRH), 
progesterone 
and estriol in 
the 
maternal/fetal 
response. 
Secondary 
 
 
 
To explore the effect of the 
MLI, versus a usual care 
group, on neuroendocrine 
risk factors of preterm birth 
(CRH, progesterone, and 
estriol) from baseline to 
end-of treatment.   
Neuroendocrine 
responses (CRH, 
progesterone, and 
estriol) 
previously 
demonstrated as 
causally related 
to the antecedents 
The neuroendocrine 
measures are potential 
causal mechanisms linking 
the changes in the 
antecedents to the improved 
infant health outcomes.   
CRH, 
progesterone 
and estriol are 
all part of the 
maternal fetal 
responses to 
stress, anxiety, 
and depressive 
symptoms. 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS 
OF ACTION 
and to the infant 
health outcomes.  
Tertiary/Exploratory  
 
 
 
To explore the effect of the 
MLI on infant birth 
outcomes (gestational age, 
birthweight, NICU 
admission). 
These are 
clinically 
important events 
for the infants in 
the study to show 
a possible 
treatment effect.  
 
 
Health outcomes of the 
infants after usual care or 
after treatment with the 
intervention to further 
determine efficacy.   
 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
 
Hypothesis 1a: Participants in the 6-week MLI will have decreased depressive symptoms, anxiety, 
stress, and disengaged coping, and increased active coping compared to UC at the end of treatment 
and after 6 weeks. 
Hypothesis 1b: The effects of MLI versus UC on depression, anxiety, stress, acculturative stress, 
and coping will be mediated by psychological flexibility and moderated by acculturation. 
Hypothesis 2a: Compared to UC, MLI participants will have significantly lower mean levels of 
CRH over time, from baseline to the end of treatment. 
Hypothesis 2b: Compared to UC, MLI participants will have significantly higher progesterone 
levels and lower estriol levels (resulting in higher progesterone/estriol ratios) over time, from 
baseline to the end of treatment. 
Hypothesis 3: Compared to UC, infants of mothers in the MLI group will have longer gestational 
ages, greater birth weights, and fewer NICU admissions. 
 
Design of Trial. Building on our data and findings from previous studies, we believe that testing 
the MLI in this phase 2 trial is both feasible and justified. The intervention is expected to lead to 
significant reductions in distressing psychological symptoms, with the potential to decrease the 
incidence of preterm births (PTBs). We propose conducting a parallel group, randomized 

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controlled trial (RCT) comparing the efficacy of the MLI to Usual Care (UC). This phase 2 trial 
will include psychological assessments at pre-intervention, post-intervention, and 6 weeks after 
the completion of the sessions to evaluate the effectiveness of the MLI compared to routine 
prenatal care. Our clinical team member (CTMB) will recruit eligible pregnant Latina and African 
American women, who are between 14- and 20-weeks' gestation, from the Greater Houston area. 
We chose this gestational age because it is late enough to minimize the risk of miscarriages, yet 
early enough to potentially mitigate biological responses associated with preterm birth. The MLI 
group sessions will be held weekly for 1-1/2 hours over a 6-week period, in person at the MLI 
office (Suite 303, 7580 Fannin Drive, Houston). Participants will have the option to attend makeup 
sessions if they are unable to attend the regularly scheduled ones. For those who cannot meet in 
person, sessions can be conducted via Zoom. Alternatively, we offer the option to meet via 
telehealth using an encrypted electronic platform to ensure the safety and privacy of the group. 
The MLI group sessions will be provided in both English and Spanish to meet participants' 
language needs. To minimize the risk of cross-group contamination, we will ensure that UC 
participants are scheduled at times when MLI group sessions are not in progress. 
 
Random Assignment. The random assignment of participants to the groups was conducted using 
GraphPad software, which utilizes its built-in randomization tool. This process ensures that 
participants are randomly assigned to different groups, minimizing bias and providing a fair 
distribution across the study groups. If necessary, the randomization can be repeated using the 
same settings to maintain consistency. The assignment of all groups is securely stored in a database 
protected by the statistician, with groups numbered 1 to 42/45. This information will be shared 
with the CTMB and the research team on the day of randomization, once the process is complete. 
We considered two methods for random assignment: 1) randomly assigning individuals to either 
the MLI or UC groups, and 2) randomly assigning pre-formed groups to either the MLI or UC. 
We chose to randomize participants individually, ensuring that each person is independently 
assigned to either the MLI or UC group. This approach minimizes potential contamination across 
treatments by allowing the study to be conducted in a controlled manner, facilitating effective 
follow-up throughout the post-treatment period. We recognize that in order to form groups with 
sufficient participants, some individuals may need to wait briefly before beginning their group 
treatment, based on the date of randomization, which is scheduled to occur once a month. The 
CTMB, who is blinded to group assignments to avoid bias, conducts baseline intake assessments. 
After participants have been consented, completed their intake/baseline assessments, and had their 
biological measures, the CTMB will inform them of their group assignment and schedule them for 
either MLI or UC. Our first group began in September 2021, and we have adjusted session formats 
to accommodate participants, offering varying types of sessions based on their availability and 
needs. The randomized group assignments are securely stored in a restricted database, accessible 
only by the database manager or statistician, and remain confidential until the day of 

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randomization. 
 
Number of study groups and duration of intervention. Considering the possibility of refusals 
and exclusions, we initially anticipated recruiting approximately 6 women every 6 weeks. In the 
first year, recruitment began in the fourth month after funding, with the first group randomized to 
the intervention or UC after 6 women were recruited. We successfully recruited 3 groups in the 
first year. For years 2-5, we propose forming multiple groups per year, with 6 to 8 women per 
group, aiming to recruit a total of 238 women over 5 years across both the MLI and UC groups. 
This estimate accounts for a ~20% attrition rate. To reach our enrollment target of 238 women, we 
estimate screening 378 women. Data collection for infant outcomes will occur 4-8 weeks after the 
final data collection at 32-36 weeks of gestation for the participants. 
 
Rationale and Justification for Recruiting African American Women in the Study in 
Addition to Latinas. Since September 2021, we have been prescreening African American 
women at their first obstetrical visit using the same criteria applied to Latina women for inclusion 
in the study. It is critically important to include African American women in this intervention, as 
they exhibit higher levels of emotional distress compared to Latina women. By incorporating 
African American women into the study, we aim to ensure that each group retains at least 6 
participants by initially recruiting 9-10 women. Given that 3-4 women typically drop out of the 
group sessions, expanding our recruitment pool is essential to meet the study's milestones. The 
consistently higher emotional distress scores among African American women underscore the 
need for MLI as a crucial component of their prenatal care. 
 
 
The Intervention. Table 2 gives module content, processes, and goals for the MLI.  
Table 
2.  
MLI Content, Processes & Goals 
 
# 
Session Content 
ACT/PST Processes 
Goal of Topics 
1 
A. Impact of stress on physical and emotional wellbeing 
B. Strategies to deal with stress: 
Externalize, Visualize, Simplify, Acceptance 
C. Introduce values - Identify values in various life domains 
Identify and manage stress 
 
Identify values 
Defuse from stress to avoid 
biological responses 
Identification of valued life 
areas 
2 
A. Identify and describe barriers that impact problem-solving 
skills: negative feelings, negative thinking, feelings of 
hopelessness 
B. Defusion exercises: learn to look AT thoughts rather than 
FROM them. 
C. Introduce and practice two problem solving skills to   live 
according to identified values 
D. Introduce “Stop, slow down, think and act” and rational 
problem solving 
Identify barriers to solving 
problems 
 
Defusion 
Understand barriers to 
achieving values 
 
Problem solving ways to get 
around the barriers 
 

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The techniques from Acceptance and Commitment Therapy (ACT) encourage individuals to 
experience difficult thoughts and feelings rather than avoid them. Paired with mindfulness, 
cognitive defusion helps women acknowledge troubling thoughts and feelings and observe them 
from a distance rather than accepting them as literal truths (e.g., “I can’t handle having another 
baby.”). The goal is to change the impact of distressing thoughts and feelings, rather than 
eliminating them, which may in turn alter biological responses in the body. Indeed, mindfulness 
alone has been associated with reduced distress (109) and changes in the brain (110). Problem-
Solving Therapy (PST) techniques include making effective decisions, generating creative 
solutions, and identifying barriers to reaching one’s goals. We made cultural modifications to the 
MLI, such as considering family roles and hierarchies, incorporating culturally relevant metaphors, 
and including mindfulness exercises, to make it more beneficial for pregnant Latinas. The 
intervention consists of six weekly sessions, starting between 14-20 weeks' gestation and 
continuing to 21-27 weeks' gestation, each lasting approximately 1 ½ hours. This session length 
aligns with other intervention studies using Cognitive Behavioral Therapy (CBT) during 
pregnancy and was supported by feedback from our pilot sessions. Participants in the MLI group 
will receive a handbook in either English or Spanish, containing space for reflection and activities 
to complete at home. We have also extensively refined our facilitator handbooks. Conducting the 
MLI in group settings is feasible, acceptable, and advantageous because it is cost-effective, fosters 
group support and social network building (113), and encourages positive role modeling (113). A 
recent meta-analysis (114) found no significant differences in effectiveness between individual 
and group formats for CBT. 
 
Rationale for the use of NP or CNMs. Authors of systematic reviews (115,116) recommend the 
use of CNMs/NPs to improve maternal mental health. They argue that there is a great need for 
innovative ways to provide effective mental health interventions for pregnant women. NPs scope 
of practice includes the treatment of mental health (117). Interventions such as Creating 
Opportunities for Personal Empowerment (COPE) (118-121) (a 2nd generation CBT) have 
successfully used registered nurses as well as NPs as facilitators with good outcomes. NPs were 
3 
A. Introduce & practice generating alternative solutions to 
overcome barriers to reach value-related goals 
B. Strategies: a. Quality principle; b. Deferment principle; c. 
Getting unstuck 
Committing to Action 
Identification of obstacles to 
problem solving  
Define alternatives to solve 
problems 
4  
A. Predict Consequences of Alternatives; 
B. Generate Pros and Cons    
Evaluation of solutions 
Psychological flexibility 
Acceptance 
Determine the best solution; 
Possible reevaluation if no 
best solution 
5 
Develop an Action Plan, carry plan out; Monitor, evaluate, 
reward self 
Commitment 
Development of an action 
plan 
6 
Summary of content and skills & how to apply in one’s life 
Note: Mindfulness exercises are at the end of each session 
 
Review of content and plan 
to apply in everyday life 

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also effective in our pilot studies. NPs/CNMs are ideal facilitators because of their knowledge of 
both physical and mental health aspects of pregnancy; a focus on both may reduce prematurity 
risks. NPs or CNMs will facilitate the groups with participants.   
 
Control or Usual Care (UC) Group. Participants in the UC group will receive standard, 
traditional individual prenatal care following the schedule of visits recommended by the American 
College of Obstetricians and Gynecologists. This group allows us to determine whether the MLI 
is more effective in reducing psychosocial risks compared to the usual information and advice 
provided as part of current prenatal care practices. If women in the UC group require mental health 
treatment, they will be provided with a list of resources, and their obstetrician will be notified. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The selection of usual care for the comparison group is based on the current baseline for prenatal 
care, i.e., no intervention for mental health, unless pathology is diagnosed and then treatment is 
referred. The emotional well-being of the participants is not routinely assessed in care, unless it is 
a simple screen for depression. Inclusion of a usual care group allows for evaluation of treatment 
outside of prenatal care (i.e., psychologist or psychiatrist), including use of medications. The 
purpose of the intervention is to ensure emotional wellbeing as part of the patient’s prenatal care. 
As noted, we will avoid MLI group sessions when the usual care group is being seen to avoid 
contamination from one group to the other. 
4.3 
JUSTIFICATION FOR INTERVENTION 
Please see section on study design for the justification for data collection related to infant outcomes 
and length and number and frequency of intervention contacts.  The intervention was originally 
designed for the Hispanic culture, as described earlier, but has since been expanded to include 
African American women as well. To meet the minimum acceptable participation criteria, 
participants must attend at least 3 out of the 6 sessions. In our data analysis, we will account for 
the number of sessions attended. 
4.4 
END-OF-STUDY DEFINITION 
A participant is considered to have completed the study if she has fulfilled the following criteria: 
completed the baseline (first) assessment, attended at least 3 intervention sessions (for those in the 
experimental group), and completed both the F1 (second) assessment and the F2 (third and final) 
6-week follow-up assessment for either group. 
  
The end of the study for a participant is defined as the completion of all required assessments for 
both the UC and MLI groups. 

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5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
Inclusion criteria are: a) providing informed consent; b) ability to read and speak English or 
Spanish; c) pregnant at 14-20 weeks' gestation with one fetus, intrauterine pregnancy, gestational 
dating will be reviewed before enrollment via ultrasound administered per standard of care; d) self-
identification as African American or Hispanic; e) age 18 to 45 years; and f) currently living in the 
U.S.; g) Medicaid or other government supported insurance or low income (less than $35,000 per 
year); h) women who score 10 or greater on the CES-D (possibility of mild depression) OR 5 or 
greater on the Generalized Anxiety Disorder-7 scale (GAD-7) (mild anxiety), OR greater than or 
= to 14 on the PSS (mild stress); i) willingness to adhere to the MLI regimen or usual care regimen.  
Justification for prescreening scores of the participants: The aim of this project is to both 
prevent and treat problems that Latina and Black pregnant women may have with their emotional 
health. 
5.2 
EXCLUSION CRITERIA 
All individuals meeting any of the exclusion criteria at baseline will be excluded from study 
participation as noted below: 
Exclusions after initial review of the electronic health record (EHR) are: a) major systemic 
infections such as HIV, hepatitis; b) <18 years of age or >45 years of age; c) enrollment in a 
prenatal program such as the Nurse Family Partnership; d) severe cognitive or psychiatric 
impairment per judgment of providers, that precludes cooperation with study protocol; e) inability 
to read English or Spanish. Women who develop GDM after enrollment in the study will remain 
in the study. Development of hypertension or preeclampsia, pyelonephritis, or GDM will be 
considered an effect modifier in analysis of infant outcomes. Current antidepressant use will not 
be exclusionary and will also be used as an effect modifier. Further rationale for the exclusion 
criteria is: 
• 
Only singleton pregnancies are included as the mechanisms of PTB are thought to differ with 
multiples. 
• 
We do not exclude participants based on language (English or Spanish) spoken. We expect 
heterogeneity in language spoken and expect that there may be women who use both 
languages. Our prior study findings indicate that the risk of PTB is greatest among English-
speaking and bilingual women, although we believe that all women will receive benefit from 
the MLI. 
• 
Girls <18 are excluded as the intervention is designed to improve emotional wellbeing and 
quality of life in mature adults; girls <18 may not be cognitively ready for the adult 

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intervention and may need an intervention tailored to their stage of development. Girls under 
18 also have a different set of risks than women over 18 years of age. 
• 
We will control the use of progesterone treatment statistically. 
• 
Women who develop gestational diabetes after enrolling in the study will remain in the study. 
• 
At enrollment or during the study, anyone who is prescribed antidepressant or anti-anxiety 
medications will be eligible for the study. We will make note of it and control it in analysis. 
If a participant is referred for individual therapy, we will obtain that data from the prenatal 
record and control for that in the analysis. 
5.3 
LIFESTYLE CONSIDERATIONS 
N/A 
5.4 
SCREEN FAILURES 
Our prescreening of the prenatal chart and the use of three different instruments to include 
participants that at least have mild anxiety, depression or stress should be sufficient to avoid the 
need for screening failures.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Sample and Setting: Dr. Chavez, based in the Texas Medical Center in Houston, sees 
approximately 40 new pregnant women each month. In our previous study conducted within this 
practice, 61% of the patients had scores of 10 or higher on the CES-D, indicating mild depression, 
while 30% had scores of 14 or higher, indicating moderate to severe depression. For this study, we 
will use the CES-D to prescreen participants for scores of 10 or up to 35, the GAD-7 for scores of 
5 or greater (mild anxiety), and the Perceived Stress Scale (PSS) for scores of 14 or greater. Given 
the potential for refusals and exclusions, we conservatively estimate recruiting 6 women every 6 
weeks. In the first year, recruitment began in the fourth month after funding, and we successfully 
recruited 3 groups of 6-9 women each. For years 2-5, we propose forming 8 groups per year, with 
6-8 women per group, aiming to recruit a total of 238 women across both the MLI and UC groups 
over the 5-year period. This target accounts for an estimated 20% attrition rate, and we anticipate 
screening at least 378 women to achieve our enrollment goal. In the same obstetrical practice from 
our last study, 66% of the women spoke English, 24% were bilingual, and 10% spoke only Spanish. 
Participation in our previous study was high, with 80-85% of those approached gave a consent to 
participate in the study. We plan to offer the MLI in separate sessions to accommodate English 
speakers, bilingual English/Spanish speakers, and Spanish-only speakers. 
 
Procedures for Recruitment, Consent, and Data Collection. Our clinical team member (CTMB) 
will coordinate with the staff of participating obstetricians to identify Latina and African American 

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pregnant women prior to, or withing the timeframe of 14-20 weeks at their first prenatal visit (as 
long as the women are 14-20 weeks at the time of randomization). This will be done by the staff 
giving out pre-screening questionnaires (the CES-D, GAD-7 and PSS) and an informative 
brochure to pregnant women within the appropriate gestational range. We will place flyers and 
posters as informational materials in the office and the restrooms. The CTMB will either be present 
at the practice site making the feasibility of ongoing screening easier, or they will be monitoring 
pre-screening scores remotely and be available by phone for any issues that arise. If the participant 
is interested in the study, the CTMB will review the exclusion/inclusion criteria for the participant 
and the scores for the CES-D, GAD-7 and PSS. The CTMB will plan to obtain informed consent 
as soon as possible, either in-person or via telephone consent. The CTMB will then schedule a 
time for the participant to come to the office and complete the baseline assessments and 
corresponding biological samples. To ensure blindness of the data, the CTMB will transfer the 
electronic data directly from the preprogrammed tablets to the REDCAP database, that is Internet 
based. Identification of which group the participants are in will be after 4-8 participants have 
consented. The CTMB will then let the participants know what group they are in.  
Post-treatment data collection will occur immediately after the last MLI session or 21-27 weeks 
for the UC group, and again at the final 6-week follow-up between 32-36 weeks. If the participant 
does not come for a data collection visit, the CTMB will make every effort to contact them via 
approved contact methods to reschedule the appointment.  
Rationale for the six-week follow-up data collection after treatment: We believe it is important 
to assess potential ongoing effects of the MLI to decrease psychological risks in the third trimester 
prior to delivery.  
Processes for Each Group: The MLI office will serve as a place to host group sessions. Groups 
will run every week for 6 weeks with MLI sessions lasting about 90 minutes. The last session 
(Session 6) will require an additional 1.25 hours of time to accommodate completion of study 
questionnaires and biologic data collection (blood, urine). If the participant is attending the final 
session via Zoom, the CTMB will schedule a separate time, within the appropriate time frame, for 
them to come in and complete their study questionnaires and biological data collection. For the 
UC, the third data collection will require about 1.25 hours for data collection. The final data 
collection for both groups will require about the same amount of time. 
The MLI office has comfortable chairs and available paid parking. Sessions will start at 14-20 
weeks gestation and continue through 21-27 weeks gestation. A 14-20-week window will avoid 
women who may miscarry yet will be early enough in the 2nd trimester to enhance the probability 
of expected outcomes. Each session will be led by a NP facilitator or CNM (certified nurse 
midwife) trained to deliver the intervention. 
Either a trained phlebotomist or nurse will data collect after session 6, performing venipuncture, 
testing urine specimens, and ensuring samples are in the -40-degree freezer as soon as possible. 
The same process for biologic samples and questionnaire data collection will be followed for both 

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groups. As much as possible, we will hold all sessions at the same time of day throughout the study 
to control diurnal variability. The phlebotomist and CTMB RN have been trained by the PI in the 
collection and safe storage/transport of biological samples. Samples will be stored in a -40-degree 
freezer at the MLI office. The serum samples designated for estriol and progesterone will either 
be kept at the MLI office to be ran by a trained CTMB or sent to the University of Texas Medical 
Branch (UTMB) to be ran by the staff there. The serum samples designated for CRH will be stored 
at the MLI office until it is appropriate to send them to Australia to be ran in the lab of Laureate 
Professor Roger Smith by him and his team.To avoid biased results, the CTMB will administer 
questionnaires using an electronic tablet device but will not participate directly with the groups. 
We will clarify questions only, not discuss answers. For infant health data, a CTMB, who also 
works for the participating obstetrician, will enter delivery data from the delivery records directly 
into an Excel database on an encrypted shared drive. 
 
Retention and Missed Sessions: We will take inspiration from a protocol that resulted in 87% 
retention in prior studies (122): 1) prior to obtaining informed consent, the CTMB will read with 
the women a Commitment Pledge to complete all 6 MLI sessions and all 3 data collection 
appointments (122); 2) we will collect alternative contact information for each participant and 
conduct multiple reminder phone calls if needed (123); 3) the NP or CNM will report group 
attendance to the CTMB and data manager who will track attendance across the duration of the 
study and create a weekly and summative attendance/attrition report; 4) the PI will review 
attendance and attrition rates weekly; 5) the NP or CTMB will phone or text any participant who 
misses a session to encourage continuation and assist with issues related to attending the sessions; 
6) incentives will be provided for the completion of data collection instruments at baseline, during 
treatment, and follow-up; and also 7) maintain positive working relationships with family 
members. To evaluate participants’ satisfaction with the content and delivery of each session, 
Likert-type measures will be used unofficially after sessions 1 and 3 (to allow for real-time 
improvements to the intervention) and officially at the end of the session 6. We will use these 
evaluations to examine factors that may affect attrition, such as timing, place, and day of the week, 
as well as overall satisfaction with the program. The CTMB will coordinate with the NP or CNM 
to call participants that miss a session. The NP or CNM will review with them individually, or in 
a group format (depending on the number of participants who missed the session), the session over 
Zoom will use the content of the facilitator’s manual. Although the make-up session will not have 
the benefit of the in-person group, it will at least allow the participant to keep up with the 
knowledge from the module. We will use data about missed sessions to assess dose response. 
Although we have had a successful experience recruiting out of Dr Chavez’s private practice, if 
our recruitment is delayed or we are not able to retain the participants as hoped, we are recruiting 
new physicians to have their patients participate in the study. This will allow a backup plan should 
we not meet milestones at the end of any year.  

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Once challenging participants are identified, the research team will engage in considerable 
brainstorming/problem-solving to ensure the completion of the intervention and any follow-up 
visits in a large diverse city such as Houston. We have a designated cellphone for participants to 
text or call to reschedule/schedule/confirm upcoming visits. The project cellphone will be covered 
by the CTMB during office hours. Project staff send messages or make calls in each participant’s 
preferred medium (i.e., e-mail, text, or voice call). At baseline, via the IRB-approved consent form, 
we will obtain permission to contact participants via multiple methods (e.g., email, text, or voice 
call). These communication methods will begin within hours of a missed visit. 
If the CTMB is not successful with engaging/reengaging a participant, then a senior member of 
the team, such as Dr Ruiz, will reach out to participants to problem-solve missed visits. Further, 
we may contact other family members or friends (i.e., “locators” identified during the consent 
process). To increase adherence, appropriate incentives (e.g., monetary) commensurate with 
participants’ time and effort are planned for distribution. Research staff will make every effort to 
let participants know they are valued and appreciated. Staff will use non-judgmental language and 
try to help participants enjoy their time in the study as other methods to improve retention. 
Feedback from the pilot study has been incredibly positive related to acceptability and retention. 
 
Participant Incentives: The CTMB will ensure that each participant receives payment via a 
reloadable Clincard after each data collection visit, even if a participant does not complete the 
entire study, and regardless of which group they are in. The participants will receive a reloadable 
Clincard that is refilled at these intervals: $60 after completing the baseline data collection visit 
(14-20 weeks of pregnancy), $70 at the follow-up 1 data collection visit (21-27 weeks of 
pregnancy) and $50 at the final follow-up 2 data collection visit (32-36 weeks of pregnancy). If a 
participant misses a data collection appointment, the CTMB will contact them as to when they can 
come in for make-up appointment. Therefore, for either usual care or MLI group, a participant 
may potentially receive a total of $180 for participating. The participants may also be eligible for 
parking reimbursement for MLI group sessions due to the cost of parking at the medical center.   
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
6.1 
STUDY 
INTERVENTION(S) 
OR 
EXPERIMENTAL 
MANIPULATION(S) 
ADMINISTRATION 
6.1.1 
STUDY 
INTERVENTION 
OR 
EXPERIMENTAL 
MANIPULATION 
DESCRIPTION 
 
Please see Table 2 under Study Design for session content and goals of the intervention for 
the MLI.  

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6.1.2 ADMINISTRATION AND/OR DOSING 
We will hold six weekly group sessions starting at 14-20 weeks' gestation and ending at 21-
27 weeks gestation. They will last ~1 ½ hours and will be at the MLI office lobby or delivered 
via Zoom. Our primary plan is that the participants will interact with each other face to face 
and the NP or CNM interventionist in the MLI group. We may have to use Zoom or another 
electronic delivery method as needed if they cannot attend in person. We consider 3 sessions 
to be the minimum for a full dose intervention. Six is the average number of sessions delivered 
in other intervention studies using CBT in pregnancy and was supported in feedback from our 
pilot sessions. Transportation will be provided if the participant requires assistance. We will give 
participants in the MLI group a participant handbook in either English or Spanish that has space 
for reflection and activities to complete at home. We have refined our facilitator handbooks 
extensively. Conducting the MLI with groups is feasible, acceptable, and advantageous as it is a) 
cost-effective, b) allows for group support and building a social network (113), and c) encourages 
good role modeling (114). A recent meta-analysis (114) found no significant differences in 
effectiveness in individual versus group formats for CBT. 
6.2 
FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
Training and Intervention Fidelity. The NP or CNM training for the MLI was initially facilitated 
by Dr Villarreal (expert in ACT processes) and PI Ruiz. The sequential training elements were the 
following: a) The NP or CNM completed knowledge assessments pre-independent study and post-
in-person training. b) 5-hours of independent study, including reading the MLI manual and 
relevant empirical literature, plus listening to audio recordings about different components of ACT 
or PST, c) experiential training on how to facilitate an MLI including ACT and PST strategies. A 
brief didactic review of the MLI model, a description of important teaching strategies, and an 
explanation of logistical considerations for an MLI group encompassed part of the training. The 
significant and lengthy portion of the training focused on the practice facilitation of MLI group 
sessions through role-plays, plus troubleshooting common problems that occur during groups with 
challenging group members, and d) 6-weeks of consultation in which the group facilitator 
implements the MLI for the first time, conducts group sessions, and does audio/video recordings 
of their group sessions. Dr Villarreal had initially reviewed the videotaped sessions and given 
feedback. The DNP that has been trained and conducted the sessions for the last three years is now 
helping the PI with the training of any new NPs or CNMs.  
The PI has conducted education and training sessions for the CTMB and personnel at the clinical 
practice site about the study, eligibility, data collection, questionnaire administration, protocol for 
venipuncture and blood specimen management, and testing and storage of urine samples. 
Universal precautions were taught for safe sample handling. The PI has trained the CTMB to 

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collect data from the prenatal chart and hospital record and to evaluate the effectiveness and 
accuracy of data collection while ensuring blinding.  
We will monitor and evaluate the fidelity of content delivery for MLI groups, conducted in person, 
or via Zoom. We currently have a psychiatric nurse practitioner that is assigned to evaluate the 
content delivery two times for every 6 sessions for fidelity. She will give feedback to the NP after 
the session. Thus, audiovisual recordings are important for quality control and are mandatory for 
the participants. Compliance with the protocol will be monitored using the MLI Fidelity Checklist 
(adherence scale).  
 
Measures to Minimize Bias: Randomization and Blinding 
Random Assignment. The random assignment of participants to groups was conducted using 
GraphPad software, which utilizes its built-in randomization tool to ensure that participants are 
randomly assigned, minimizing bias and ensuring a fair distribution across the study groups. All 
group assignments are securely stored in a database protected by the statistician, with groups 
numbered 1 to 42/45. This information will be shared with the CTMB and the research team on 
the day of randomization, once the process is complete. We considered two methods for random 
assignment: 1) assigning individuals randomly to either the MLI or UC groups, and 2) assigning 
pre-formed groups to either the MLI or UC. We chose to randomize participants individually, 
ensuring that each person is independently assigned to either the MLI or UC group. This approach 
minimizes potential contamination across treatments, allowing the study to proceed in a controlled 
manner and facilitating effective follow-up throughout the post-treatment period. To ensure 
adequate group sizes, some participants may need to wait briefly before beginning their group 
treatment, based on the date of randomization, which is scheduled to occur once a month. Our first 
group began in September 2021, following a 3-month period of training and startup, with session 
formats adjusted to accommodate both in-person and electronic delivery as needed. In this setup, 
the CTMB and the NP involved in the intervention, data collection, and follow-up for participants 
who miss sessions are aware of the group assignments. However, these personnel are strictly 
instructed not to share participant ID numbers with the PI or Co-Investigators unless explicitly 
approved by the PI. The statistician, who manages the randomization process, remains blinded to 
the specific participant numbers associated with each group and has no direct exposure to the 
individual participants. Laboratory samples are labeled with participant ID numbers and are 
blinded to the laboratory technician. The Principal Investigator (PI), Dr. Ruiz, will make every 
effort to remain blinded to group assignments to ensure unbiased data analysis. While the 
psychiatric NP (consultant) reviews videotapes of the intervention and is thus aware of who is in 
the intervention group, they are not informed of which participant numbers are associated with the 
data. 
 

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6.3 
STUDY 
INTERVENTION/EXPERIMENTAL 
MANIPULATION 
ADHERENCE 
The CTMB will initiate and maintain an Excel spreadsheet of all participants in the MLI group as 
well as the UC group. After each group session, the CTMB will check with the NP as to who the 
participants were and log them on the participation log. Mandatory is completion of the two times 
the questionnaires are to be given and the laboratory assessments for two different times. An active 
participant will need to have completed 3 MLI sessions if in the experimental group, both sets of 
questionnaires for two different data collections, and two sets of laboratory assessments. 
6.4 
CONCOMITANT THERAPY 
N/A 
 
6.4.1 RESCUE THERAPY 
N/A 
 
7. STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION 
OF 
STUDY 
INTERVENTION/EXPERIMENTAL 
MANIPULATION 
When a subject discontinues from the MLI group but not from the study, the participants will 
complete the remaining study procedures (i.e., completion of second round of questionnaires and 
laboratory assessment).   
If a deleterious clinically significant finding is identified (including, but not limited to changes 
from baseline) after enrollment, the PI, Dr Ruiz, will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event 
(AE). 
 
The data to be collected by the CTMB at the time of study intervention discontinuation will include 
the following: 
• 
The reason(s) for discontinuing the participant from the intervention, and methods for 
determining the need to discontinue. 
• 
If the participant is due to complete assessments within 2 weeks of being discontinued from 
the study intervention, those assessments will be administered at the time of discontinuation; if the 
next scheduled assessments are more than 2 weeks from the discontinuation date, the discontinued 

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participant will wait for the next scheduled assessment. Thereafter, the participant will be included 
in all future scheduled assessments, even though not participating in the intervention. 
7.2 PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
FROM 
THE 
STUDY 
Participants have the right to withdraw from the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
• 
Significant non-compliance with the study intervention, such as attending fewer than 
3 out of 6 sessions in the MLI group, or unwillingness to complete required 
questionnaires and laboratory assessments. 
• 
Lost to follow-up: If the study staff is unable to contact the participant after multiple 
attempts (see Section 14.3, Lost to Follow-Up). 
• 
Medical events or conditions that arise during the study, where continued 
participation may not be in the best interest of the participant or may require additional 
treatment that could interfere with the interpretation of the study results (e.g., severe 
depression requiring hospitalization). 
• 
Newly identified exclusion criteria or conditions not previously recognized that 
disqualify the participant from further study participation. 
The reason for any participant’s discontinuation or withdrawal will be documented in the Case 
Report Form (CRF). Participants who sign the informed consent form and are randomized into 
either group will continue to be monitored in the "intent to treat" group unless they formally request 
in writing to be removed from the study.  
7.3 LOST TO FOLLOW-UP 
A participant is considered lost to follow-up if they fail to attend 3 sessions of the MLI, and study 
staff is unable to re-establish contact after at least three attempts. 
The following steps will be taken if a participant misses a required study visit: 
• The CTMB or Licensed Advanced Practice Nurse/NP will attempt to contact the 
participant and reschedule the missed visit within the following week, possibly offering the 
session via electronic means. They will also counsel the participant on the importance of 
adhering to the assigned visit schedule and assess whether the participant wishes to 
continue in the study. 
• Before declaring a participant lost to follow-up, the CTMB will make every reasonable 
effort to re-establish contact, including making three telephone calls and, if necessary, 
sending a certified letter to the participant’s last known address or using other locally 
appropriate methods. All contact attempts will be recorded in the participant’s study file. 
• If the participant remains unreachable, they will be considered withdrawn from the study, 
with "lost to follow-up" as the primary reason. 

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Attrition, it refers to the loss of participants during the course of a study, which can occur due to 
dropouts, withdrawal, loss to follow-up, or other reasons. The impact of attrition is significant 
because it can lead to reduced statistical power and potentially biased results if the attrition is not 
random.  
 
Please see also Retention and Missed Visits  
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1 ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
See also Procedures for Recruitment, Consent and Data Collection  
 

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D.10. 
Study 
variables. 
Demographic 
variables 
include age, marital status, 
education, insurance provider 
or self-pay, gravida, para, 
number of abortions, country 
of birth, years living in the 
US, 
primary 
language, 
residence in public housing, 
and number of times the 
participant has moved within 
the last year. Data on income, 
housing, mobility, and type of 
insurance will be used to 
assess socioeconomic status. 
This data will be collected by 
the CTMB after training by 
the PI. 
We 
will 
not 
ask 
the 
participants if they have a 
social security number, to 
satisfy the concerns of the 
scientific review related to 
Human Subjects. Obstetric 
variables. A CTMB who has 
been professionally trained in 
obtaining obstetrical histories 
by working in an obstetrical 
setting, 
will 
collect 
obstetrical 
history, 
last 
menstrual 
period 
and 
ultrasound determination of 
expected 
date 
of 
confinement, 
height/weight 
for BMI, infections (vaginal or systemic), medications (particularly SSRI use or progesterone) and 
other prescription or illegal drug use, and any other medical risk factors for PTB (GDM, 
preeclampsia, history of PTB, etc.) from the prenatal chart. This data will be obtained only after a 
HIPPA consent has been signed seeking permission of review of the entire prenatal chart. The 
Table 3. Self-Report Questionnaires for Data Analysis 
Measure 
Purpose; 
Variable 
type 
Times Measured 
Baseline =16-20 
wks. 
Time 2 = 20-26 wks. 
Time 3 = 26-32 wks. 
# 
Items 
α 
Spanish 
MASII 
Multidimensional 
Acculturation 
Scale (127) 
Cultural 
identity; 
Language 
proficiency: 
Moderator 
Baseline  
22 
.78-
.93 
Yes 
CESD (129) 
Depressive 
symptoms 
Primary 
outcome 
Prescreen, Baseline; 
Midtreatment (19-23 
weeks) for MLI 
group only.   
Time 2 and 3 
20 
.85- 
.94 
Yes 
GAD-7 (130) 
Anxiety; 
Primary 
outcome 
Prescreen, Baseline,  
Time 2 and 3 
7 
.89 
Yes 
PSS Perceived 
Stress Scale (34) 
Global 
measure of 
stress 
Primary 
outcome 
Prescreen, Baseline,  
Time 2 and 3 
10 
.79 
Yes 
MASI 
Multidimensional 
Acculturative 
Stress Inventory 
(33) 
Measure of 
acculturative 
stress 
Primary 
outcome 
Baseline,  
Time 2 and 3 
36 
.93 
Yes 
The Brief Cope 
(131) 
Positive 
versus 
negative 
coping; 
Primary 
outcome 
Baseline,  
Time 2 and 3 
28 
.86-
.89 
Yes 
Multidimensional 
Psychological 
Flexibility 
Inventory (MPFI) 
132)  
Psychological 
Flexibility 
Mediator 
Baseline, Mid-
treatment (19-23 
weeks), 
Time 2 and 3 
22 
.97 
Yes  
Group Climate 
Questionnaire 
(133) 
Measures if 
the group is 
engaged, 
conflictual, or 
avoiding 
interaction; 
Covariate 
Time 2 taken by NP 
and participants 
12 
.9 
N/A 

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HIPPA consent will be obtained with informed consent as it is completed at the initiation of the 
participation in the study. 
Psychological and acculturation measures, listed in Table 3, will be scored as recommended by 
scales’ authors. The team has used these questionnaires extensively. These measures have been 
tested in Spanish without problems or reliability issues. We will also ask women if they have been 
receiving any mental health therapy as well. The NP or CNM facilitator will assess group climate 
themselves, and for the participants, using the Group Climate Questionnaire (134) at follow-up 1. 
This questionnaire will be used as a covariate in analysis. Hormones, cotinine. We will collect all 
biological samples at baseline (14-20 weeks), follow-up 1 (21-27 weeks), and follow-up 2 (32-36 
weeks). After drawing the blood, we will centrifuge the blood and separate into aliquots of plasma 
as done in our previous studies. The blood is stored in the laboratory at the MLI office in a -40-
degree centigrade freezer. The serum samples designated for estriol and progesterone will either 
be kept at the MLI office to be ran by a trained CTMB or sent to the University of Texas Medical 
Branch (UTMB) to be ran by the staff there. The serum samples designated for CRH will be stored 
at the MLI office until it is appropriate to send them to Australia to be ran in the lab of Laureate 
Professor Roger Smith by him and his team. Progesterone and estriol will be run in batches with 
ELISAs. We will prepare plasma samples for CRH with Aprotinin 500 IU/ml added. We plan to 
analyze CRH by radioimmunoassay. Urine samples will be pre-screened for cotinine (with 1-Step 
Rapid Nicotine test) and THC (with 1-Step Rapid THC Marijuana test) for both groups at all data 
collection points. We have focused on testing the hormones at the timepoints mentioned as our 
previous results, as well as others, justify these critical time periods for the neuroendocrine 
response. We will follow the World Health Organization’s Good Laboratory Practices (136).  
Infant outcomes. Pregnancy duration will be recorded in completed weeks and days, and 
birthweight will be recorded in grams. We will collect data on any NICU admissions. In Ruiz-
R01-NR07891, we collected data on ~200 babies without difficulty from Dr Chavez’s delivery 
records. This data will include diagnoses for the infant, especially those linked to pregnancy 
complications. We will collect data on medically indicated PTB versus spontaneous PTB, as well 
as early term births (37-39 weeks). We will use gestational age as a continuous variable as longer 
gestation, even among term infants, benefits both cognitive and motor development (137). Infant 
sex as a covariate of biological and infant outcomes. Evidence indicates that male infant 
outcomes may be more affected by prenatal adversities than female infant outcomes (138), 
including a link between maternal prenatal depression and impaired neonatal motor behavior in 
male infants (139) and a link between prenatal maternal depression and increased anxiety seen in 
females (140).   
8.2 SAFETY ASSESSMENTS 
Please see section 9.9 for detailed discussion of safety assessments and protections. 

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8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
Adverse Event:  Any unfavorable and unintended sign associated with the MLI, regardless of 
whether it is considered related to the intervention. These include such things as revelations of 
child abuse, domestic violence. Adverse events also include “unanticipated problems” of any 
nature (e.g., psychological or social harm) and will be designated as unrelated, related, probably 
related, or possible related (see below). 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
Serious adverse event:  Any adverse event that is fatal or life threatening, is permanently disabling, 
requires inpatient hospitalization, or results in a congenital anomaly or birth defect. Examples 
include suicidal attempts, homicidal attempts, drug overdoses. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
SEVERITY OF EVENT 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
Life-threatening event:  Any adverse event in which the subject is at immediate risk of death from 
the reaction as it occurs. This does not include a reaction that, if it were to occur in a more serious 
form, might cause death. Although unlikely for this behavioral intervention, an example of this 
might be a severe allergic reaction during data collection or while participating in the group 
sessions. 
 
Unexpected event:  Any adverse event that is not identified in nature, severity, or frequency in the 
investigator brochure, study protocol, consent form; or the event was more serious than 
anticipated. An example of an unexpected event would be a participant falling. 
RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 

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Definitely Related:  An adverse event that has a timely relationship to the administration of the 
investigational study procedure and follows a known pattern of response for which no alternative 
cause is present. 
 
Probably Related:  An adverse event that has a timely relationship to the administration of the 
investigational study procedure and follows a known pattern of response, but for which a potential 
alternative cause may be present. 
 
Possibly Related:  An adverse event that has a timely relationship to the administration of the 
investigational study procedure and follows no known pattern of response, but a potential 
alternative cause does not exist. 
 
Unrelated:  An adverse event for which there is evidence that it is related to a cause other than the 
study procedure; in general, no timely relationship to the administration of the procedure exists, or 
if so, the event does not follow a pattern of response and an alternative cause is present. 
EXPECTEDNESS  
An AE or suspected adverse reaction is considered "unexpected" if it is unlikely to occur in the 
study population, or it is unlikely to occur at the severity that has been observed. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the 
risk information previously described for the study procedures. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention 
of study personnel during data collection visits, during a group session for participants of the MLI 
group, or during a prenatal care visit with the physician. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the Adverse Event 
Reporting Form as delineated in this section. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study procedures 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on the study will be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. Documentation of onset and duration of each 
episode will be maintained for AEs characterized as intermittent. 

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The CTMB will record events with start dates occurring any time after informed consent is 
obtained until 7 days (for non-serious AEs) or 42 days (length of group sessions) (for SAEs) after 
the last day of study participation.  At each data collection visit for the UC group, the CTMB will 
inquire about the occurrence of AE/SAEs.  For the UC Group, events will be followed for outcome 
information by the prenatal care provider until resolution or stabilization. The NP/CNM will 
follow up with a MLI group member privately after a group session weekly, or as needed, for AEs. 
The following are the Adverse Event Reporting Forms for the study: 
 
Participant ID # ______________ 
 
Name:  ____________________ 
Date:  _____________________ 
 
Phone:  ___________________ 
 
1.  Reason for follow up on site after a session:   
Verbal admission of child abuse during group session. (unsolicited response if present) 
Time period:  _______ 
 
NP discussed with participant.  (enter summary of discussion) 
 
 
Follow up: 
 
____ Participant was notified of need for further follow up with child protective services 
____ Documentation of referral (include who made the call, date and time of the call, who was 
contacted, and brief summary of information relayed): 
 
3. Reason for follow up on-site after a session:  
 
2. Verbal admission of domestic violence during group session. (unsolicited) 
 
Time period: _______ 

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Discussed with participant: (enter summary) 
 
Follow up: 
_____Participant was given resource list 
_____Safety plan was generated 
_____Participant refused assistance at this time 
 
 
3.. Reason for followup on site either after a group session or after a data collection session: 
Unsolicited comments that indicate an actual or potential adverse event (generally). 
Discussed with participant (enter summary) 
Follow up: 
 
8.3.5 ADVERSE EVENT REPORTING  
ADVERSE EVENT REPORTING: 
Serious adverse events will be reported to the IRB and DSMB within 48 hours of learning of the 
event. Unexpected adverse events that are not serious, but may be associated with the intervention, 
will be reported to the IRB and NIH no later than 30 days after the event on an annual basis. After 
considering the symptoms, a decision will be made by the PI in conjunction with the DSMB, if 
indicated, whether to recommend that the participant stop the intervention and/or refer the 
participant for further evaluation. The PI is responsible for reporting adverse events to the DSMB 
within 48 hours of the occurrence. The DSMB will determine whether said events are related to 
the study. All adverse events, serious and non-serious, will be fully documented on the appropriate 
Adverse Event (AE) Reporting Form.  For each adverse event, the investigator will provide the 
onset, duration, intensity, treatment, required, outcome and action taken. Serious adverse events 
are not expected to occur during this study. 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
In consultation with the PI, the CTMB will be responsible for conducting an evaluation of a serious 
adverse event and shall report the results of such evaluation to the NIH and the Institutional Review 
Board (IRB) as soon as possible. This reporting should be no later than 10 working days after the 
investigator first learns of the event. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  

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N/A  
8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
8.3.9 REPORTING OF PREGNANCY  
N/A all participants are pregnant. 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
Unanticipated Problems include problem situations that arise during the course of a study but are 
not directly related to study procedures.  
 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human 
Research Protections (OHRP). OHRP considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of 
the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents and (b) the characteristics of the 
participant population being studied. 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
These UPs may include loss of data or data collection documents and psychological distress related 
to the intervention or control condition (as described above). 
8.4.2  UNANTICIPATED PROBLEMS REPORTING  
A research team member will report any unanticipated problems (UPs) to the Data Coordinating 
Center (DCC) and to the principal investigator (PI) Dr Ruiz, who will report to the reviewing 
Western-Copernicus Group Institutional Review Board (WCG IRB). The UP report will include 
the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• A detailed description of the event, incident, experience, or outcome  

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• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP. 
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• UPs that are serious adverse events (SAEs) will be reported to the IRB and to the 
DSMB/study sponsor/funding agency within 48 hours of the investigator becoming aware 
of the event.  
• Any other UP will be reported to the IRB and to the DSMB/study sponsor/funding agency 
within 14 days of the investigator becoming aware of the problem  
• All UPs will be reported to appropriate institutional officials, the supporting agency head 
(or designee), and the Office for Human Research Protections (OHRP) within 30 days of 
the IRB’s receipt of the report of the problem from the investigator] 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
N/A 
9. STATISTICAL CONSIDERATIONS  
9.1 STATISTICAL HYPOTHESES 
Primary Endpoints to Test Efficacy:  
• 
Hypothesis 1a: Participants in the 6-week MLI will have decreased depressive symptoms, 
anxiety, and stress, disengaged coping, and increased active coping compared to UC at 
end-of-treatment and after 6 weeks.   
• 
Hypothesis 1b: The effects of MLI versus UC on depression, anxiety, stress, acculturative 
stress, and coping will be mediated via psychological flexibility and acculturation.  
 
Secondary Endpoints to Test Biological Mechanisms of Efficacy and Health Outcome 
of Infants: 
• 
Hypothesis 2a: Compared to UC, MLI participants will have significantly lower mean 
levels of CRH over time from baseline to end-of-treatment.   
• 
Hypothesis 2b: Compared to UC, MLI participants will have significantly higher 
progesterone levels and lower estriol levels (higher progesterone/estriol ratios) over time 
from baseline to end-of-treatment.  
• 
Hypothesis 3: As compared to UC, infants from mothers in the MLI group will have longer 
gestational age, greater birth weight, and fewer NICU admissions. 
9.2 SAMPLE SIZE DETERMINATION 

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Table 1. Power to detect given effect sizes assuming different rates of attrition. 
 
This study is designed to have sufficient power to test the primary hypothesis in Aim 1, with 
calculations conducted using k = 1000 Monte Carlo simulations under various conditions in SAS 
9.4. Specifically, the power analysis focuses on detecting a statistically significant interaction 
between time and treatment group using generalized linear mixed models (GLMM). Table 1 
outlines the power to detect effect sizes under the following conditions: (1) a range of plausible 
attrition rates (~15%, ~20%, and ~25%); (2) a total recruitment target of 238 women; (3) a 
correlation of r = .50 between consecutive observations (e.g., baseline to week 6, week 6 to week 
12); (4) a correlation of r = .05 for all observations collected at the same time point; and (5) a 
significance level of α = .01 (after applying the Bonferroni correction across five outcomes as 
described in Hypothesis 1). In practice, statistical significance will be assessed using the false 
discovery rate (FDR) to adjust for multiple comparisons, based on the observed p-values. The 
expected effect sizes align with those observed in previous research and pilot studies. For instance, 
our pilot study (n=15) showed effect sizes for anxiety ranging from d = -.37 to d = -1.5, and for 
depression from d = -.45 to d = -.76, which are consistent with findings in other studies utilizing 
ACT. For example, McCracken (108) found a Cohen's d = 0.58 for depression using the PHQ-9 in 
an RCT (n=73) following ACT for chronic pain, and Majumdar (102) reported a medium effect 
size for group ACT (ղ2 = .07, or d = 0.55). 
 
9.3 POPULATIONS FOR ANALYSES 
Intention-to-treat analyses will be conducted using SPSS software. We will examine any missing 
data to determine whether it is missing at random. Since the proposed analyses can fully 
incorporate unbalanced data, all collected data will be utilized, even if some repeated measures are 
missing. Missing data will be managed through maximum likelihood estimation, explicit modeling 
of missingness, and/or multiple imputations, each of which is robust to data missing at random. 
We will also assess the sensitivity of the analyses to different patterns of missing data. To address 
multiple comparisons within families of tests, we will apply the false discovery rate (FDR) 
approach. 
  
Sample 
Size 
15% Attrition  
N = 200 (100/group) 
20% Attrition  
N = 190 (95/group) 
25% Attrition  
N = 180 (90/group) 
 Power 
81.1% 
86.3% 
91.6% 
78.8% 
84.5% 
90.6% 
75.4% 
82.6% 
88.6% 
Effect 
Size 
0.300 
0.325 
0.350 
0.300 
0.325 
0.350 
0.300 
0.325 
0.350 

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9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
All variables will be summarized via descriptive statistics. Categorical data will be summarized 
by frequency and percent, and continuous data will be summarized in terms of central tendency 
(i.e., mean/median) and dispersion (i.e., standard deviation). Inferential tests will rely on the 
statistical significance criterion α =.05 (two-tailed). Hypothesis tests that find values p ≤ .05 will 
be considered statistically significant. Covariates may potentially be included in statistical models; 
details of covariate inclusion are described below in Section 9.4.2.  Modeling assumptions will be 
evaluated via inspection of residual plots and formal statistical tests. Violations of assumptions 
will be addressed as needed via by transformation, robust estimation coefficient scaling, 
stratification, or model respecification. Any hypothesis tests that are unable to satisfy statistical 
modeling assumptions will be reevaluated via equivalent non-parametric tests if possible. 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINTS 
Analyses will primarily rely on generalized linear mixed modeling (GLMM) to evaluate the 
relationships between predictors and outcomes. This flexible approach allows for modeling of 
normally or non-normally distributed outcomes, specified by distribution family and link function, 
as well as longitudinal or multilevel data through the inclusion of level-2 terms for participant ID. 
Nonlinear effects can also be modeled using spline or polynomial terms. The measurement scales 
for all study outcomes are described in Section 8.1.  
For longitudinal analyses, each outcome will be modeled as a function of the treatment group, 
time, and the interaction between treatment group and time. If the interaction term is not 
statistically significant, the model will be simplified to include only the main effects. Follow-up 
tests of simple effects will be conducted to evaluate changes in each outcome over time within 
treatment groups (141, 142). Cross-sectional analyses at each time point will also use GLMM to 
model each outcome as a function of the treatment group. In all models, random intercepts will be 
included for participant ID and other multilevel data structures, such as participants within groups.  
Interaction effects will be described as significant or non-significant. If significant, the focus will 
be on the simple effects of time within each group; if non-significant, the focus will shift to models 
of main effects without the interaction. Results will be presented as parameter estimates with 95% 
confidence intervals for models that assess either main effects or within-group models of simple 
effects in the presence of a significant interaction. Graphical presentations will include plots of 
estimated marginal means of outcomes over time by group.  
Mediation analyses will investigate the indirect effects of treatment on 6-week follow-up measures 
of depression, anxiety, stress, and coping through intervening (end-of-treatment) measures of 
psychological flexibility and acculturation. These analyses will utilize Structural Equation 

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Modeling/Path Analysis with MPlus (v. 8.4) to evaluate both direct and indirect effects of 
treatment on outcomes. Indirect effects will be estimated using the product coefficient method, 
with 95% confidence intervals constructed via bootstrap resampling.  
Prior to hypothesis testing, relationships between baseline and demographic variables, treatment 
groups, and outcomes will be assessed using GLMM. Covariates that demonstrate relationships 
with both predictors and outcomes will be considered potential confounders, leading to the 
development of two models: one with and one without covariate adjustment. If covariate 
adjustment impacts inferences, both models will be reported; otherwise, the simpler model will be 
presented.  
Specific covariates to be examined as potential confounders include age, pre-pregnancy body mass 
index, gravidity, positive cotinine, positive drug screens, fetal sex, group climate scores for MLI 
sessions, concurrent behavioral therapy, acculturation scores, country of birth, SSRI or 
progesterone use, obstetrical variables such as preeclampsia, gestational diabetes, history of 
preterm birth, and infections during the periods between and during data collection and delivery, 
as well as the frequency of intervention attendance. For the MLI group, the number and type of 
sessions, whether phone-based for missed sessions or in-person, will be examined as moderating 
dose-response effects of treatment.  
Assumptions of statistical modeling will be evaluated via inspection of residual plots and formal 
statistical tests. Missing data will be handled through methods such as multiple imputation or 
maximum likelihood estimation, ensuring that all available data are utilized. Sensitivity analyses 
will be conducted to evaluate the robustness of results under different assumptions or data handling 
methods. 
  
Finally, for a priori defined outcomes, a significance level of α = 0.05 (two-tailed) will be applied. 
The false discovery rate (FDR) correction will be used to control for Type I error in any follow-
up or post hoc tests. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The analytic details provided in Section 9.4.2. also apply to any endpoints that may be established 
post hoc.  
 
9.4.4 SAFETY ANALYSES 
N/A  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
N/A  
 

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9.4.6 PLANNED INTERIM ANALYSES  
N/A 
9.4.7 SUB-GROUP ANALYSES 
If a given baseline characteristic is determined to influence the relationship between predictors and 
outcomes via the criteria for confounding described above, that characteristic will also be 
evaluated as a potential moderator of the time x treatment interaction; in essence providing a three-
way interaction. Subgroup analyses will then evaluate the primary statistical models within each 
group, sample size permitting (model convergence may be an issue if group sizes end up being too 
small). 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
We do not plan to tabulate individual participant data. 
9.4.9 EXPLORATORY ANALYSES 
N/A 
 
10. SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS 
10.1 
REGULATORY, 
ETHICAL, 
AND 
STUDY 
OVERSIGHT 
CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks will be given 
to the participant and written documentation of informed consent will be completed prior to 
starting the study intervention.  The following consent materials are submitted with this protocol: 
a. Consent form to participate in the study 
b. HIPPA form to release prenatal record and birth record 
a. CONSENT FORM TO TAKE PART IN RESEARCH 
RESEARCH SUBJECT CONSENT FORM 
 

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TITLE: 
Reductions in Biopsychosocial Risks for Pregnant Minority Women 
and Their Infants: The Mastery Lifestyle Intervention 
 
PROTOCOL NO.: 
R01 HD101535-01A1 
 
WCG IRB Protocol #20235111 
 
SPONSOR: 
Microgen Laboratories LLC 
 
INVESTIGATOR: 
Roberta Jeanne Ruiz, Ph.D., WHCNP-BC, FAAN 
 
7580 Fannin, Suite 303 
 
Houston, TX 77054 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
713-383-7020 
 
 
RESEARCH CONSENT SUMMARY 
 
You are being asked for your consent to take part in a research study. This document provides a 
concise summary of this research. It describes the key information that we believe most people 
need to decide whether to take part in this research. Later sections of this document will provide 
all relevant details. 
 
What should I know about this research? 
Someone will explain this research to you. 
Taking part in this research is voluntary. Whether you take part is up to you. 
If you don’t take part, it won’t be held against you. 
You can take part now and later drop out, and it won’t be held against you 
If you don’t understand, ask questions. 
Ask all the questions you want before you decide. 
 
How long will I be in this research? 
We expect that your taking part in this research will last until the birth of your baby. 
 
Why is this research being done? 
The purpose of this research is to determine the helpfulness of group counseling to reduce risks 
for you and your baby. These risks are related to stress, anxiety, and depression (how you feel). 

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The group counseling is called, “the Mastery Lifestyle Intervention” (MLI).  
 
What happens to me if I agree to take part in this research? 
If you decide to take part in this research study, the general procedures include: 
• Getting assigned to the investigational MLI treatment group (the study treatment PLUS 
usual prenatal care) or the Usual Care (UC) group  
• Filling out questionnaires about how you feel and how you handle change, 3 different 
times. You may skip any questions on the questionnaires that you do not want to answer. 
• Having your blood drawn and urine collected, 3 separate times (baseline, follow-up 1, 
follow-up 2) 
 
If you are assigned to the MLI treatment group, you will still receive usual prenatal care, but 
additional procedures include: 
•  Attending 6 group MLI sessions with a Nurse Practitioner (NP) or Certified Nurse 
Midwife (CNM) and other group participants. Group sessions will be videorecorded  
 
Could being in this research hurt me? 
Discomforts for the MLI group:  
• There is a risk that the MLI may not be as good as current therapy for anxiety, depression, 
or stress.   
• There is a risk that you could have some embarrassment, guilt, fear, sadness, or other 
psychological feelings from taking part in the MLI group because sensitive emotions or 
problems may be revealed. To decrease this risk, we have a list of resources we can give 
you should you have excessive discomfort.   
• Your privacy is important and your participation in this study will be kept confidential. 
However, absolute confidentiality cannot be guaranteed. You will be assigned a study 
number with your name protected.  At the first MLI session, we will talk about the rules to 
lower the risk of your being in the study in order to help keep your privacy. ** 
 
**Exceptions to the confidentiality rule include: 1) if you reveal child or elder abuse, the session 
leaders are required by law to report that to child or adult protective services; and 2) if you indicate 
suicidal or homicidal thoughts, we may disclose this information to your physician to protect you 
or others in accordance with Texas law.  
 
Discomforts for either group (MLI or UC) include:   
• There is a small risk of mild pain or discomfort, bruising and swelling from your blood 
drawn at the puncture site. It is possible that you might become dizzy or faint.   

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• There is a small risk of infection from the blood draw sites. We will use disinfectant to 
clean the area where we will draw blood and will use a sterile needle to reduce the risk of 
infection. We will apply pressure with sterile gauze to avoid bruising and infection and 
help you to avoid fainting.   
• You may get tired or bored when we are asking you questions, or you are completing 
questionnaires. You do not have to answer any question you do not want to answer.   
• You may have mild emotional discomfort from answering the surveys. We have a list of 
resources that we can provide if this discomfort continues. 
• There is a small risk of a loss of confidentiality. We will work hard to keep your 
confidentiality. We will do our best to maintain your privacy throughout your time in the 
study.  
 
This research is unlikely to harm your pregnancy or fetus in any way.   
 
Will being in this research benefit me? 
The most important benefits that you may expect from taking part in this research, particularly 
when in the MLI group, include: 
• MLI group will be led by a Nurse Practitioner or Certified Nurse Midwife, who will be 
able to help address anxieties or problems related to pregnancy 
• Improved emotional health 
• Improved coping to stressors 
• Decrease in stress, depression, and/or anxiety 
• Decreased risk for preterm birth (birth before 37 completed weeks of pregnancy) 
• Improved relationships between yourself and people close to you 
• Improved sleep quality 
 
Possible benefits to others include additional evidence-based information that may contribute to 
reducing perinatal depression, preterm births, and number of admissions to the neonatal intensive 
care unit (NICU). 
 
What other choices do I have besides taking part in this research? 
Instead of being in this research, you may choose to consult with your physician and ask for a 
referral to a licensed therapist. Another option is to decline participating (which you can do at any 
point) and continue receiving usual prenatal care.  
 
What else should I know about this research? 
Other information that may be important for you to consider so you can decide whether to take 

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part in this research is that the MLI group requires attendance to 6 weekly meetings, so barriers to 
your attendance (work conflicts, school conflicts, childcare conflicts, vacation, transportation, etc.) 
will need to be considered. The clinical research team members will work with you to 
accommodate the attendance conflicts, but early notice helps ensure accommodation.  
 
MLI sessions will be videotaped to ensure quality and to confirm that the NP or CNM is running 
the session effectively. Recordings will be reviewed by members of the research team who are 
trained to review recordings and may include experts located at other research facilities also 
involved in this research. All study recordings will be kept in locked file cabinets and/or password 
protected computers with only study staff having access to them. Information from the recordings 
may be published or shared in study reports as a group to help describe the sessions and how they 
were conducted, but your name or other data that might reveal who you are will not be revealed in 
any reports or writings that may result from this study. 
 
 
DETAILED RESEARCH CONSENT 
 
You are being invited to take part in a research study.  A person who takes part in a research study 
is called a research subject, or research participant.  
 
What should I know about this research? 
Someone will explain this research to you. 
This form sums up that explanation. 
Taking part in this research is voluntary. Whether you take part is up to you. 
You can choose not to take part. There will be no penalty or loss of benefits to which you are 
otherwise entitled. 
You can agree to take part and later change your mind. There will be no penalty or loss of 
benefits to which you are otherwise entitled. 
If you don’t understand, ask questions. 
Ask all the questions you want before you decide. 
 
Why is this research being done? 
The purpose of this research is to determine the helpfulness of group counseling to reduce risks 
for you and your baby. These risks are related to stress, anxiety, and depression (how you feel). 
The group counseling is called, “the Mastery Lifestyle Intervention” (MLI). The potential for 
improved emotional health by being in the MLI group may lower the risk for preterm births, a 
known risk for your baby to be sick at birth. 
 

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About 238 subjects will take part in this research. 
 
How long will I be in this research? 
We expect that your taking part in this research will last until the birth of your baby. 
 
For the UC group, there are three (3) visits for data collection, which may take about an 1–1 ½ 
hours each, for a total of 4 ½ hours.  
 
For the MLI treatment group, there are an extra six (6) group visits that may take about 1 – 1 ½ 
hours each. This totals to about 6–9 hours for group sessions and 4 ½ hours for data collection 
until 32–36 weeks of your pregnancy. 
 
What happens to me if I agree to take part in this research? 
If you decide to take part in this research study, the general procedures include: 
• Getting assigned to the MLI treatment group (the study treatment PLUS usual prenatal 
care) or the Usual Care (UC) group  
• Filling out questionnaires about how you feel and how you handle change, 3 different 
times. You will be requested to fill out all the questionnaires three different times during 
your pregnancy (baseline, follow-up 1 and follow-up 2) and it will take about 90 minutes 
or less each time. You may skip any questions on the questionnaires that you do not want 
to answer. 
• Having your blood drawn and urine collected, 3 separate times (baseline, follow-up 1, 
follow-up 2) 
 
If you are assigned to the MLI treatment group, you will still receive usual prenatal care, but 
additional procedures include: 
•  Attending 6 group MLI sessions with a Nurse Practitioner (NP) or Certified Nurse 
Midwife (CNM) and other group participants. Group sessions will be videorecorded. All 
of your group sessions will be held at the same location. If you change OB/GYN providers, 
you will no longer be able to participate in the study and will not need to attend group 
sessions anymore. Your group session will be held at the following site: 
 
Microgen Laboratories LLC, Mastery Lifestyle Intervention 
7580 Fannin Street, Suite 303 
Houston, Texas 77054 
 
You will be put into a study group by chance (like a coin toss). You have an equal (50 out of 100) 
chance of being placed in each group. You cannot choose your study group. You will be notified 

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of which group you are assigned to by a member of the research team. 
 
The Usual Care (UC) group will receive standard prenatal care without attending the MLI sessions. 
The study will still collect biological data (blood, urine), psychological data (questionnaires), and 
birth and newborn outcome data from the UC group. 
 
Activities of the study will occur from the time of consent until the birth of your baby. The timeline 
is as follows: 
• Signing recruitment documents, including informed consent and patient rights to privacy 
and confidentiality (HIPAA) 
• Baseline data collection (14–20 weeks of pregnancy) – Includes blood draw, urine 
sample and electronic questionnaires on a tablet. This step is completed for both groups. 
• MLI Treatment Group Start – This is only for the participants randomized to the 
MLI group. MLI group sessions include participating in the MLI therapy content with an 
NP or CNM and other group participants. Groups will take place in a conference area at 
the Microgen Laboratories MLI location mentioned above. 
• 1st Follow up data collection (21–27 weeks of pregnancy) – Includes blood draw, urine 
sample, and electronic questionnaires on a tablet. This step is completed for both groups. 
• 2nd Follow up data collection (32–36 weeks of pregnancy) – Includes blood draw, urine 
sample and electronic questionnaires on a tablet. This step is completed for both groups. 
 
What are my responsibilities if I take part in this research? 
If you decide to take part in this research study, the general procedures include: 
• Getting assigned to the MLI treatment group (the study treatment PLUS usual prenatal 
care) or the Usual Care (UC) group  
• Filling out questionnaires about how you feel and how you handle change, 3 different 
times. You may skip any questions on the questionnaires that you do not want to answer. 
• Having your blood drawn and urine collected, 3 separate times (baseline, follow-up 1, 
follow-up 2) 
 
If you are assigned to the MLI treatment group, you will still receive usual prenatal care, but 
additional procedures include: 
•  Attending 6 group MLI sessions with a Nurse Practitioner (NP) or Certified Nurse 
Midwife (CNM) and other group participants. Group sessions will be videorecorded  
 
If you take part in this research, you will be responsible to:  
• Make sure members of the research team have current contact information to be able to 

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contact you (they will reach out to you when data collection times are coming up) 
• Maintain appointment times for data collection and MLI sessions 
• Disclose to members of the research team if you are currently receiving any other 
psychological therapy or psychiatric care 
• Disclose to members of the research team any medications, if any, you are using or begin 
using 
• Disclose to members of the research team any medical conditions you currently have or 
may develop throughout the pregnancy 
• Describe any problems or concerns regarding the study to the investigator promptly 
• Notify study team members if you cannot attend an appointment time or need to reschedule 
• Immediately contact the investigator or immediately seek medical attention should you 
begin experiencing thoughts of hurting yourself, hurting others or killing yourself or others  
 
Could being in this research hurt me? 
Discomforts for the MLI group:  
• There is a risk that the MLI may not be as good as current therapy for anxiety, depression, 
or stress.   
• There is a risk that you could have some embarrassment, guilt, fear, sadness, or other 
psychological feelings from taking part in the MLI group because sensitive emotions or 
problems may be revealed. To decrease this risk, we have a list of resources we can give 
you should you have excessive discomfort.   
• Your privacy is important and your participation in this study will be kept confidential. 
However, absolute confidentiality cannot be guaranteed. You will be assigned a study 
number with your name protected.  At the first MLI session, we will talk about the rules to 
lower the risk of your being in the study in order to keep your privacy. ** 
 
**Exceptions to the confidentiality rule include: 1) if you reveal child or elder abuse, the session 
leaders are required by law to report that to child or adult protective services; and 2) if you indicate 
suicidal or homicidal thoughts, we may disclose this information to your physician to protect you 
or others in accordance with Texas law.  
 
Discomforts for either group (MLI or UC) include:   
• There is a small risk of mild pain or discomfort, bruising and swelling from your blood 
drawn at the puncture site. It is possible that you might become dizzy or faint.   
• There is a small risk of infection from the blood draw sites. We will use disinfectant to 
clean the area where we will draw blood, and will use a sterile needle to reduce the risk of 
infection. We will apply pressure with sterile gauze to avoid bruising and infection and 

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help you to avoid fainting.   
• You may get tired or bored when we are asking you questions, or you are completing 
questionnaires. You do not have to answer any question you do not want to answer.   
• You may have mild emotional discomfort from answering the surveys. We have a list of 
resources that we can provided if this discomfort continues. 
• There is a small risk of a loss of confidentiality. We will work hard to keep your 
confidentiality. We will do our best to maintain your privacy throughout your time in the 
study.  
 
This research is unlikely to harm your pregnancy or fetus in any way.   
 
Will it cost me money to take part in this research? 
Taking part in this research requires no additional cost, only your time. 
 
Parking fees accrued during data collection or MLI session visits will be reimbursed by the study. 
 
Will being in this research benefit me? 
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits to you (particularly when in the MLI treatment group) include improved 
emotional health, improved coping to stressors, improved relationships with people close to you, 
improved sleep quality and a decrease in stress, depression, and/or anxiety. These benefits may 
continue even after the study ends. You may also experience a decreased risk for preterm birth 
(birth before 36 completed weeks of pregnancy), which may reduce risk of your baby being 
admitted to the neonatal intensive care unit (NICU).  
 
Possible benefits to others include additional evidence-based information that may contribute to 
reducing perinatal depression, preterm births, and number of admissions to the NICU. 
 
What other choices do I have besides taking part in this research? 
Instead of being in this research, you may choose to consult with your physician and ask for a 
referral to a licensed therapist. Another option is to decline participating (which you can do at any 
point) and continue receiving usual prenatal care.  
 
What happens to the information collected for this research? 
Your private information and your medical record will be shared with individuals and 
organizations that conduct or watch over this research, including: 
The research sponsor, Microgen Laboratories, LLC 
People who work with the research sponsor 

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Government agencies, such as the National Institutes of Health (NIH) 
WCG IRB, the Institutional Review Board (IRB) that reviewed this research 
Companies engaged with Microgen Laboratories, LLC to commercialize the MLI 
 
We may publish the results of this research. However, we will keep your name and other 
identifying information confidential. 
 
We protect your information from disclosure to others to the extent required by law. We cannot 
promise complete secrecy. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
Data or specimens collected in this research might be de-identified and used for future research or 
distributed to another investigator for future research without your consent. 
 
Who can answer my questions about this research? 
If you have questions, concerns, or complaints, or think this research has hurt you or made you 
sick, talk to the research team at the phone number listed on the first page.  
 
This research is being overseen by WCG IRB. An IRB is a group of people who perform 
independent reviews of research studies. You may talk to them at 855-818-2289 or 
clientcare@wcgclinical.com if:  
You have questions, concerns, or complaints that are not being answered by the research team. 
You are not getting answers from the research team. 
You cannot reach the research team. 
You want to talk to someone else about the research. 
You have questions about your rights as a research subject. 
 
What if I am injured because of taking part in this research? 
If you are injured or get sick because of being in this research study, call the study doctor 
immediately. Free treatment has not been arranged, and no other payment for injury is routinely 
available from the study doctor or sponsor. However, emergency treatment and professional 
services are available to you. You should call Dr. Roberta J. Ruiz at the study phone number, 713-
383-7020, to tell her of your injury. You will not give up any of your legal rights by signing this 
consent form.   
 

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Can I be removed from this research without my approval? 
The person in charge of this research can remove you from this research without your approval. 
Possible reasons for removal include: 
It is in your best interest 
You have a side effect that requires stopping the research 
You need a treatment not allowed in this research 
You have a miscarriage or induced abortion 
The research is canceled by the DHHS or the sponsor 
You are found to have an infection in your blood 
You are unable to keep your scheduled appointments 
You transfer your prenatal care to a different OB provider 
 
We will tell you about any new information that may affect your health, welfare, or choice to stay 
in this research. 
 
What happens if I agree to be in this research, but I change my mind later? 
If you decide to leave this research, contact the research team so that the investigator can 
understand the purpose of your decision to stop participating. The investigator will also make sure 
you have received all the incentives that you have provided data for and update your OB physician 
that you have removed yourself from the study.  
 
If you decide to leave the research early, there may be risks with this decision. This may include 
reduced ability to cope with stressors as well as you did while in the study, and you will not be 
able to receive incentive payments for data that was not provided for the study’s use.   
 
Will I be paid for taking part in this research? 
For taking part in this research, you may be paid up to a total of $180.00. Your compensation will 
be broken down as follows: 
$60.00 after collection of the baseline data (collected at 14 – 20 weeks of pregnancy) 
$70.00 after collection of 1st follow-up data (collected at 21- 27 weeks of pregnancy) 
$50.00 after collection of 2nd follow-up data (collected at 32 – 36 weeks of pregnancy) 
 
You will receive payments after each data collection visit, even if you do not complete the entire 
study. Participants in both groups, intervention and usual care, will receive payment. 
 
If you drop out of the study before the next data collection, you will not receive incentives for the 
remainder of data collection visits 
 

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We will need your name and current address to receive your incentive payment. The incentive 
payments will be added to a reloadable ClinCard gift card and given to you. Every time you have 
complete data visits, your ClinCard gift card will be reloaded with the incentive amount for that 
visit. 
 
Your specimens (even if identifiers are removed) will not be used for commercial profit.  
 
Statement of Consent:  
 
Your signature documents your consent to take part in this research. 
 
 
 
 
 
Signature of adult subject capable of consent 
 
Date 
 
 
 
 
 
Signature of person obtaining consent 
 
Date 
 
My signature below documents that the information in the consent form and any other written 
information was accurately explained to, and apparently understood by, the subject, and that 
consent was freely given by the subject. 
 
 
 
 
 
Signature of witness to consent process 
 
Date 
 
b. HIPAA Privacy Authorization Form  
 **Authorization for Use or Disclosure of Protected Health Information (Required by the 
Health Insurance Portability and Accountability Act, 45 C.F.R. Parts 160 and 164) ** 
 
Participant Name: ___________________________  
Participant Date of Birth: ______/______/______ 

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I give permission for my obstetrical healthcare provider to use and disclose (share) the 
protected health information described below to Roberta Jeanne Ruiz, PhD, WHCNP-BC, 
FAAN, Primary Investigator of this research project.  
The study staff will get the medical information of you and your baby. For example: past and 
present medical records, research records, records of correspondence between you and your 
provider’s office (as it pertains to this research), records of your prenatal and study visits, 
records of your outcome/birth and records of you baby’s outcome/birth.  
The study staff will share the records generated from this research, regulatory agencies such 
as DHHS (Department of Health and Human Services), and the IRB (Institutional Review 
Board). 
This information is shared so the research can be conducted and properly monitored. The 
people receiving this information may be re-disclosed without your permission. 
If you do not provide permission to use your information, you cannot be in the study. 
The permission will not end unless you cancel it.  
You may cancel your permission by sending written notice to the study staff on the first page 
of the main consent document.  
Any information collected before you withdraw your permission may still be used.  
This authorization for release of information covers the period of healthcare from: June 2021 
to June 2026. 
I authorize the release of my complete prenatal health record (including records relating to 
mental healthcare, communicable diseases, HIV or AIDS, and treatment of alcohol or drug 
abuse). 
This authorization shall be in force and effect until the end of the research study (June 2026), 
at which time this authorization expires. 
I understand that I have the right to revoke (cancel) this authorization, in writing, at any time. 
I understand that a revocation (cancellation) is not effective if any person or entity has 
already acted, relying upon this authorization. 
I understand that my treatment, payment, enrollment, or eligibility for benefits will not be 
controlled by whether or not I sign this authorization. 
I understand that the health information used in this research study as a result of this 
authorization may no longer be protected by federal or state law.  
I understand that when giving my contact information (phone number and email address) I am 
consenting to the research personnel contacting me via these methods, including leaving 
voicemails on the provided phone number.  
 
 
_________________________ 
____________________________ ____/____/____ 

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    Participant Name (Print)                      Participant Name (Signature)                  Date  
_________________________ 
____________________________ ____/____/____ 
    Witness Name (Print)                              Witness Name (Signature)                  Date  
 
CONSENT PROCEDURES AND DOCUMENTATION 
Our plans for recruitment and consent were informed by results of our pilot work.  
• 
Our CTMB will coordinate with the staff of participating obstetricians to have pre-screening 
questionnaires, and an informative brochure, handed to potential participants upon signing-in 
for their appointment. The brochure contains a phone number for our CTMB, who can be 
contacted during office hours to answer any questions the potential participant may have. 
• 
The CTMB will either be in-person at the office of the participating obstetrician, or will be 
available remotely to answer questions and review eligibility information for potential 
participants. This will allow us to reach as many participants as possible. 
• 
We will place flyers and posters as informational materials in the office and the restrooms.  
• 
The CTMB will ensure the discussion of the study, determination of eligibility, and obtaining 
informed consent are done in a manner respectful of the potential participant’s privacy. These 
conversations may happen in-person or over the phone. 
• 
We will also ask participants to sign a Personal Health Information (HIPPA) release to 
examine their medical records, as well as those of their future infant. The participating 
obstetrician will also allow a CTMB (from either the MLI office or their office) to collect data 
from the enrolled participants’ prenatal records (after participants have consented) that are 
relevant to the medical confounders to be controlled for in the study. They will collect data 
from the prenatal records and the birth records, and will be able to link the participant’s release 
to their study identification number for data entry purposes. 
Processes for Each Group.  
One group will run at a time, either MLI or UC. The MLI groups are given at the MLI office. 
Groups will run for 6 weeks with MLI sessions lasting about 90 minutes. A separate Zoom session 
will be conducted in Spanish with a fluent Spanish speaking NP or CNM throughout all sessions. 
This is because there is a much smaller group of Spanish speakers and it would be difficult to 
integrate them with the English speakers. The last session (Session 6) will require an additional 
1.25 hours of time to accommodate completion of study questionnaires and biologic data collection 
(blood, urine). For the UC, the second data collection will require about 1.25 hours for data 
collection. The final data collection for both groups will require about an hour or so of time. 

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The office for the MLI has comfortable chairs and couches and available paid parking. Sessions 
will start at 14-20 weeks' gestation and continue through 21-27 weeks' gestation. A 14-20-week 
window will avoid women who may miscarry yet will be early enough in the 2nd trimester to 
enhance the probability of expected outcomes. Each session will be led by an NP or CNM 
facilitator trained to deliver the intervention. 
Either a trained phlebotomist or nurse will data collect at Session 6 and will perform venipuncture 
and test urine specimens. As much as possible, we will hold all sessions at the same time of day 
throughout the study to control for diurnal variability. The CTMB has been trained by the PI in the 
collection and safe storage/transport of biological samples. All specimens will be kept in a -40-
degree freezer at the MLI office laboratory. To avoid biased results, the CTMB will administer 
questionnaires using an electronic tablet device but will not participate directly with the groups. 
We will clarify questions only, not discuss answers. For infant health data, the CTMB will enter 
delivery data from the hospital charts directly into an encrypted Excel database that will be then 
used for the statistical database. The same process for biological samples and questionnaire data 
collection will be followed for both groups. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigators, NICHD, and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and NICHD and will 
provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance of study staff to the protocol (i.e., significant protocol violations) 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met. 
• 
Determination of futility 
 

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The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the funding agency, sponsor, IRB, or other relevant regulatory or oversight 
bodies (OHRP, DSMB). 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This 
confidentiality is extended to the data being collected as part of this study. Data that could be used 
to identify a specific study participant will be held in strict confidence within the research team. 
No personally identifiable information from the study will be released to any unauthorized third 
party without prior written approval of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), regulatory agencies may inspect all 
documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) for the participants in this study. The clinical study site 
will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor/funding 
agency requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored on an encrypted shared drive. The PI and Co-Is will be able to 
log and access the data. Rather, individual participants and their research data will be identified by 
a unique study identification number. The study data entry and study management systems used 
by clinical sites will be secured and password protected. At the end of the study, all study databases 
will be de-identified and archived. 
 
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies  
It is NIH policy that the results and accomplishments of the activities that it funds should be made 
available to the public (see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all 
mechanisms used to share data will include proper plans and safeguards for the protection of 
privacy, confidentiality, and security for data dissemination and reuse (e.g., all data will be 

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thoroughly de-identified and will not be traceable to a specific study participant). Plans for 
archiving and long-term preservation of the data will be implemented, as appropriate.  
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored on a shared drive. After the study is 
completed, the de-identified, archived data will be transmitted to and stored at Microgen 
Laboratories, for use by other researchers including those outside of the study.  
 
With the participant’s approval, and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at Microgen Laboratories. These samples could be 
used to research the causes of premature birth, its complications and other conditions for which 
individuals with reactivated viruses such as Epstein Barr Virus and Cytomegalovirus are at 
potential increased risk, and to improve treatment. Microgen Laboratories will also be provided 
with a code-link that will allow linking the biological specimens with the phenotypic data from 
each participant, maintaining the blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
bio sample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data and/or samples will be provided through 
Microgen Laboratories. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Institutional Monitor  
Roberta Jeanne Ruiz, PhD, 
Senior Clinical Health Research 
Scientist 
Raymond Stowe, PhD, CEO of 
the Microgen Laboratories 
Microgen Laboratories, LLC  
Microgen Laboratories, LLC 
7580 Fannin Street Suite 303  
Houston, TX 
903 Texas Avenue La Marque 
Tx 
281-300-5265 
409-935-6700 
jruiz@microgenlabs.com 
rpstowe@microgenlabs.com 
 

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Direct Report 
Team Member 
Responsibilities 
NIH 
PI Ruiz 
Oversight of all team members and 
training for human subjects including but 
not limited to rigor with data collection; 
fidelity of the intervention; ensure use of 
decision algorithm for referral of women 
reporting violence or depression; Ensure 
attainment of milestones; and overall 
quality of investigation. Prepares IRB 
application and monitors for any adverse 
events. Prepares progress report for 
NICHD. 
PI Ruiz 
Consultant:  
Dr. 
Misty 
Richmond 
PMHNP 
Oversee MLI groups for effectiveness and 
any problems with group sessions; 
Interventionist initial training for ACT 
and PST and group dynamics 
PI Ruiz 
Interventionist training: 
Dr. Liza Rivera, PI Ruiz 
Serves as a role model for group sessions  
PI Ruiz 
Co-I  
Dr. Darpan Patel 
Oversee analysis of laboratory tests for 
blood and urine-ensuring quality results, 
Available as back up for running ELISA 
samples as needed and ensures safe 
laboratory practices.  
PI Ruiz 
CTMB/ Clinical Research 
Nurse Coordinator: 
Amanda 
Thomas 
(RN, 
BSN)  
Ester Godbold (RN, BSN) 
Assists Dr Ruiz in operationalization of 
the aims by overseeing immediate data 
and sample collection with the CRA, data 
collection for questionnaires in absence of 
the CRA; venipuncture and collection of 
urine samples as needed; assuring 
planning of groups with CRA after 
randomization, assists NPs with supplies 
and needed preparation for groups 
sessions; monitors a weekly report of 

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recruitment and retention of participants. 
Assists with progress reports and IRB 
updates. Laboratory: Organize and store 
biological samples, prepares samples and 
sets up samples needing transport to lab; 
Conduct ELISA analysis of progesterone, 
estriol and cotinine. Ester serves as a 
consultant for ensuring research integrity 
and protection of human subjects. 
PI Ruiz & 
PC 
CTMB/Clinical Research 
Associate: 
Irma Pecina  
 
Recruitment; Informed Consent; Assign 
each patient with unique de-identified ID 
number; Tracks incentives; monies used 
for mileage, parking, and taxis; Assists in 
setting up group sessions; Assists with 
solving transportation problems and 
attendance problems for data collection if 
needed 
PI Ruiz 
Data Manager/ Statistician 
onsite analysis 
Devanshi Majeethia, MS, 
BDS 
Data: 
Set-up 
database; 
ensures 
randomization 
is 
blinded 
during 
recruitment and allocation of groups after 
all participants are in a group; monitor 
missing data; Review data with PI for 
accuracy, integrity, and completeness on 
a weekly basis.  
PI Ruiz 
Co-I  
Dr. Rita Pickler 
Setup data collection for nuances related 
to infant outcomes; Review infant health 
data monthly after participants deliver; 
Consultant 
regarding 
expert 
advice 
surrounding randomized clinical trials 
PI Ruiz 
NPs 
Dr. Liza Rivera 
Conduct 
group 
sessions 
for 
the 
intervention either electronically or in 
person. 
PI Ruiz  
CTMB 
Trained phlebotomist responsible for 
obtaining biological samples (blood, 

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Laura Guzman 
urine) 
from 
participants. 
Aids 
in 
preparation and appropriate storage of 
samples post collection. 
PI Ruiz  
CTMB 
Chelsea Rodriguez 
Staff 
member 
of 
a 
participating 
obstetrician, 
accessing 
participant’s 
medical records to obtain relevant 
information for study use. 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB)/Safety 
Monitoring Committee (SMC). Members of the DSMB will be independent from the study 
conduct and free of conflict of interest. The DSMB will meet at least semiannually to assess safety 
and efficacy data from each arm of the study. The DSMB will operate under the rules of an 
approved charter that will be written and reviewed at the organizational meeting of the DSMB. At 
this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB 
will provide its input to NICHD. 
10.1.7 CLINICAL MONITORING 
The PI will monitor data accuracy and quality on the shared drive at a minimum every other week, 
as well as monitoring the training for all new staff. The PI will verify data with the data manager, 
comprehensively. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Our Co-Investigators will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion. All sites will follow a common 
quality management plan. 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as 
well as a percentage of the completed consent documents.  This review will evaluate compliance 
with GCP, accuracy, and completeness.  Feedback will be provided to the study team to ensure 
proper consenting procedures are followed.  
 
Source documents and the electronic data --- Data will be initially captured on source 
documents via electronic tablets (see Section 10.1.9, Data Handling and Record Keeping) that 

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will ultimately be entered into the study database.  To ensure accuracy site staff will compare a 
representative sample of source data against the database, targeting key data points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored 
throughout the intervention phase of the study. Procedures for ensuring fidelity of intervention 
delivery are described in Section 0, Interventionist Training and Tracking.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and 
will implement corrective actions when the quantity or nature of deviations is deemed to be at a 
level of concern. 
 
Should independent monitoring become necessary, the PI will provide direct access to all trial 
related sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection will be the responsibility of the CTMB, and the NP Interventionist at the clinical 
obstetrical site. The PI will be responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner (i.e., consent forms, HIPPA 
forms) to ensure accurate interpretation of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets 
for recording data for each participant consented/enrolled in the study.  Data recorded in the 
electronic case report form (eCRF) derived from source documents will be consistent with the data 
recorded on the source documents.  
Clinical data (including adverse events (AEs) and expected adverse reactions data) and clinical 
laboratory data will be entered into an Excel database and then exported into SPSS. The data 
system includes password protection and internal quality checks, such as automatic range checks, 
to identify data that appear inconsistent, incomplete, or inaccurate. 
STUDY RECORDS RETENTION  
Study documents will be retained for a minimum of 7 years after the last approval of a marketing 
application in an International Council on Harmonization (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the study intervention. These 

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documents should be retained for a longer period, however, if required by local regulations. No 
records will be destroyed without the written consent of the sponsor/funding agency, if applicable. 
It is the responsibility of the sponsor/funding agency to inform the investigator when these 
documents no longer need to be retained. 
10.1.10 
PROTOCOL DEVIATIONS  AND PUBLICATION AND DATA 
SHARING POLICY 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council on Harmonization Good Clinical Practice (ICH GCP), or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, 
the investigator, or the study site staff. As a result of deviations, corrective actions will be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 
It will be the responsibility of the PI to use continuous vigilance to identify and report deviations 
within 7 working days of identification of the protocol deviation.  All deviations will be addressed 
in study source documents, reported to NICHD Program Official. Protocol deviations will be sent 
to the reviewing Institutional Review Board (IRB) per their policies. The PI will be responsible 
for knowing and adhering to the reviewing IRB requirements. 
 
Publication and Data Sharing Policy  
 This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-reviewed 
journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information 
from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to 
publish results in peer-reviewed journals.  Data from this study may be requested from other 

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researchers 10 years after the completion of the primary endpoint by contacting Dr Ruiz, PI.  
Considerations for ensuring confidentiality of these shared data are described in Section 10.1.3. 
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to 
all NIH-funded research that generates large-scale human or non-human genomic data, as well as 
the use of these data for subsequent research. Large-scale data include genome-wide association 
studies (GWAS), single nucleotide polymorphisms (SNP) arrays, and genome sequence, 
transcriptomic, epigenomic, and gene expression data. 
10.1.11 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical. Therefore, any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the design and conduct of this trial. The study leadership in 
conjunction with the NICHD has established policies and procedures for all study group members 
to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
10.2 
ADDITIONAL CONSIDERATIONS 
N/A 
10.3 
ABBREVIATIONS AND SPECIAL TERMS 
The list below includes abbreviations utilized in this template. However, this list should be 
customized for each protocol (i.e., abbreviations not used should be removed and new 
abbreviations used should be added to this list). Special terms are those terms used in a specific 
way in the protocol. For instance, if the protocol has therapist-participants and patient-
participants, those terms could be included here for purposes of consistency and specificity.  
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 

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CTMB 
Clinical Team Member 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 

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SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change 
Brief Rationale 
2 
8-11-21 
Updated Consent and minor edits 
Most current consent is needed 
for the protocol 
3 
2-22-22 
Minor updates and updated consent 
Current edits are made to reflect 
changes needed as the study 
grew larger. 
4 
10-29-2023 
Updated changes in procedures and 
data management 
Addition of African American 
women to the study 
Lowered target sample from 234 to 
221 
Organizational changes have 
been necessary 
High pre-screen scoring on 
questionnaires, need for larger 
recruitment 
5 
8-27-2024 
 
Formatting changes 
 
Grammar corrections 
Clarified date ranges for milestones 
Changed reimbursement schedule, 
amounts and method 
 
Changes to recruitment process 
Changes to schema 
Changes in wording 
Revisions to suicide protocol 
 
Added debarment process 
 
Updated involved personnel 
Increased total number of 
participants 
Added definition of attrition 
Added more methods for analyzing 
data 
Corrected randomization process 
Corrected table of contents, 
section numbering, added page 
numbers 
 
Removed midpoint, 
redistributed milestone 
payments (total amount 
unchanged) 
 
 
To reflect current process 
 
 
Updated to better care for 
participants 
Per instructions from Microgen 
Laboratories, LLC 
Updated current CTMBs and 
removed Dr. Fagundes 
To account for an attrition rate 
of 20% 
 
To increase the scope of the 
study 
 

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5.1 
09-16-2024 
Removal of debarment language 
throughout protocol 
Removed as required per WCG 
IRB SOP 21 
5.1 
09-16-2021 
Removal of research cell phone 
number 713-330-9311 
Cell phone number no longer in 
use 
5.1 
09-16-2024 
Formatting correction 
Corrected field control error to 
table of contents 
 
 

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11. REFERENCES  
 
1. Hamilton, B.E., Martin, J.A., Osterman, M.J.K., Driscoll, A.K., Rossen, L.M. (2018). Births: 
Provisional Data for 2017. NVSS Vital Statistics Rapid Release Centers for Disease Control and 
Prevention, Report No. 004.  
 
2. Mukherjee, S., Trepka, M.J., Pierre-Victor, D., Bahelah, R., Avent, T. (2016). Racial Ethnic 
Disparities in Antenatal Depression in the United States: A Systematic Review. Maternal Child 
Health Journal, 20, 1780-1797. 
 
3. Hutchens, B.F., Kearney, J. (2020). Risk Factors for Postpartum Depression: An Umbrella 
Review. Journal of Midwifery and Women’s Health. Online publication January 20. 
 
4. Jarde, A., Morals, M., Kingston, S., Gallo, R., Macqueen, G.M. Giglia, L., Beyene, J., Wang, 
U., McDonald, S.D. (2016). Neonatal Outcomes in Women with Untreated Antenatal Depression 
Compared with Women Without Depression. JAMA Psychiatry, 73(8), 826-837.  
 
5. Kessler, R.C., Berlund, P, Demler, O., et al. (2003). The epidemiology of major depressive 
disorder: results from the national comorbidity survey replication. JAMA, 289(23), 3095-3105. 
 
6. Staneva, A., Bogossian, F., Pritchard, M., & Wittkowski, A. (2015). The effects of maternal 
depression, anxiety, and perceived stress during pregnancy on preterm birth: A systematic review. 
Women and Birth, 28(3), 179-193. 
7. Lilliecreutz, C., Laren, J., Sudsjok G. Josefsson, A. (2016). Effect of maternal stress during 
pregnancy on the risk for preterm birth. BMC Pregnancy and Childbirth, 16(5), Online access.  
 
8. Wadhwa, P.D., Entringer, S., Buss, C., Lu, M. (2011). The contributions of Maternal Stress to 
Preterm Birth: Issues and Considerations. Clinics in Perinatology, 38(3),351-384. 
 
9. Entringer, S., Buss, C., Wadhwa, P.D. (2015). Prenatal stress, development, health and disease 
risk: 
a 
psychobiological 
perspective-2015 
Curt 
Richter 
Award 
Winner. 
Psychoneuroendocrinology, 62, 366-375. 
 
10. Alheusen, J.L., Alvarez, C. (2016). Perinatal Depression: A Clinical UCRCate. The Nurse 
Practitioner, 41(5), 50-55. 
 

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11. Berry, J.W. (2005). Acculturation: Living successfully in two cultures. International Journal 
of Intercultural Relations, 29, 697-712. 
 
12. Ruiz, R.J., Stowe, R.P., Brown, A., Wommack, J. (2012). Acculturation and biobehavioral 
profiles in pregnant women of Hispanic origin: Generational differences. Advances in Nursing 
Science, 35, (3), E1-E10. 
 
13.  Fox, M., Entringer, S., Buss, C., DeHaene, J., & Wadhwa, P. D. (2015). Intergenerational 
transmission of the effects of acculturation on health in Hispanic Americans: A fetal 
programming perspective. American Journal of Public Health, 105(Supplement 3), S409-
S423.  
 
14. Flores,  M.E, Simonsen, S.E., Manuck, T.A., Dyer, J.M., Turok, D.K. (2012). The "Latina 
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