Received: 17 April 2018 Revised: 30 May 2018 Accepted: 16 September 2018

DOI: 10.1002/smi.2839

RESEARCH ARTICLE

Mindfulness‐based program for stress reduction in infertile

women: Randomized controlled trial
Simone F. Nery1 | Sara P.C. Paiva1 | Érica L. Vieira2 | Andressa B. Barbosa1 |

Edna M. Sant'Anna1 | Maira Casalechi1 | Cynthia Dela Cruz1 | Antônio L. Teixeira2,3 |

Fernando M. Reis1

1
Department of Obstetrics and Gynecology,
Universidade Federal de Minas Gerais, Belo
Horizonte, Brazil
2
Department of Internal Medicine,
Universidade Federal de Minas Gerais, Belo
Horizonte, Brazil
3
Department of Psychiatry and Behavioral
Sciences, University of Texas Health Science
Center at Houston, Houston, Texas
Correspondence
Fernando M. Reis, Division of Human
Reproduction, Department of Ob/Gyn,
Hospital das Clínicas, UFMG, Av. Alfredo
Balena, 110, 9° andar, Belo Horizonte, MG
30130‐100, Brazil.
Email: fmreis@ufmg.br
Funding information
Conselho Nacional de Desenvolvimento
Científico e Tecnológico, Grant/Award
Number: 465482/2014‐7
Abstract
Infertile women often experience chronic stress, which may have a negative impact
on general well‐being and may increase the burden of infertility. In this open‐label,
parallel, randomized controlled trial, infertile women aged 18–50 years (median
37 years) were assigned to an 8‐week mindfulness‐based program (MBP) or no inter-
vention. The primary outcome was stress severity measured by the Lipp's Stress
Symptoms Inventory (ISSL). Data were analyzed by modified intent‐to‐treat principle,
which included all cases available to follow‐up regardless of adherence to the inter-
vention (62 participants from the MBP group and 37 from the control group). The
median number of symptoms of chronic stress recorded in the past month decreased
from six (interquartile range 2 to 9) before the MBP to two (interquartile range 1 to 4)
after the intervention (p < 0.001, repeated measures analysis of variance with
Time × Group interaction). Depressive symptoms also decreased after MBP, whereas
general well‐being improved (p < 0.01 for both outcomes). Hair cortisol and serum
brain‐derived neurotrophic factor (BDNF) did not change significantly between
preintervention and postintervention. None of the outcomes changed significantly
in the control group. MBP was effective in reducing stress and depressive symptoms
while increasing general well‐being in infertile women.

KEY W ORDS

BDNF, cortisol, depression, infertility, mindfulness, quality of life, stress

1 | I N T RO D U CT I O N Behavioral and cognitive therapies have been used to reduce

Infertility affects about 15% of women of reproductive age (Petraglia,
Serour, & Chapron, 2013; Thoma et al., 2013). Infertile women often
experience chronic stress, which may have a negative impact on
general well‐being and may increase the burden of infertility
(Demyttenaere, Nijs, Evers‐Kiebooms, & Koninckx, 1992; Karaca &
Unsal, 2015). Chronic stress may also impair human fecundity (Lynch,
Sundaram, Maisog, Sweeney, & Buck Louis, 2014).
Trial registration number: RBR‐7by76r
stress and mitigate its consequences in different populations, including
infertile women (Verkuijlen, Verhaak, Nelen, Wilkinson, & Farquhar,
2016). Some of these therapies are based on the principle of mindful-
ness, defined as a meditation practice that cultivates present moment
awareness (Crane et al., 2017; Ludwig & Kabat‐Zinn, 2008). It com-
prises two basic fundaments, namely, focused attention and open
monitoring (Lutz, Slagter, Dunne, & Davidson, 2008). Due to its
experiential nature, the full understanding of mindfulness requires a
first‐person experience. In general, mindfulness tasks develop several
skills such as attention, awareness, and nonjudgment of events,
thoughts, and feelings (Ludwig & Kabat‐Zinn, 2008).

Stress and Health. 2018;1–10. wileyonlinelibrary.com/journal/smi © 2018 John Wiley & Sons, Ltd. 1
2 NERY
Jon Kabat‐Zinn idealized a mindfulness‐based program (MBP)
specifically targeted to relieve stress, known as mindfulness‐based
stress reduction (MBSR) that has been used since the 1980s
(Kabat‐Zinn & Chapman‐Waldrop, 1988; Miller, Fletcher, & Kabat‐
Zinn, 1995). More recently, an MBP named “mind–body skills” was
created at the Georgetown University School of Medicine in order
to promote self‐awareness, self‐reflection, and self‐care (Saunders
et al., 2007). It derived from the original MBSR intervention with the
particularities that it does not require hatha yoga as a formal medita-
tion technique and does not have an intensive, full‐day session.
This MBP has been translated to Portuguese and validated in Brazil
(Paiva et al., 2016).
The effects of MBPs can be measured by self‐report question-
naires, indicating attenuation of stress and depressive symptoms along
with improvement in quality of life (Farb et al., 2010; Farb et al., 2007;
Fjorback, Arendt, Ornbol, Fink, & Walach, 2011; Homann et al., 2012;
Li, Long, Liu, He, & Li, 2016; Paiva et al., 2016). However, whether
MBPs are effective to reduce stress in infertile women is still uncer-
tain. Previous randomized studies with less than 15 infertile women
per group have shown potential benefits of MBPs on “perceived
stress” (Shahrestani, Qanbari, Nemati, & Rahbardar, 2012) and “rumi-
nation” (Feili, Borjali, Sohrabi, & Farrokhi, 2012), whereas a more
robust study found increased pregnancy rate among women randomly
assigned to a mind/body program during their first in vitro fertilization
(IVF) treatment (Domar et al., 2011). Stress measures have also been
shown to improve after cognitive behavioral therapy in women with
functional hypothalamic amenorrhea (Michopoulos, Mancini, Loucks,
& Berga, 2013) and after a MBP in women with polycystic ovary
syndrome (Stefanaki et al., 2015), two diagnoses that frequently
overlap with infertility.
Cortisol is the paradigmatic chronic stress hormone and responds
to the activation of the hypothalamic‐pituitary‐adrenal axis (Lee, Kim,
& Choi, 2015). Cortisol can be measured in blood, saliva, or hair
samples. Although blood and salivary cortisol levels have circadian
fluctuations, hair cortisol accumulates continuously over the process
of hair growth, becoming an integrated measure of cortisol levels
during months (Harkey, 1993; Russell, Koren, Rieder, & Van Uum,
2012; Sharpley, McFarlane, & Slominski, 2011; Stalder et al., 2017).
According to a recent meta‐analysis, chronic exposure to stress is
associated with increased hair cortisol levels, which do not reflect
the degree of perceived stress but do correlate with physical measures
such as systolic blood pressure (Stalder et al., 2017).
Brain‐derived neurotrophic factor (BDNF) is a member of the neu-
rotrophic factor family that is released during acute stress response,
especially in limbic brain areas (Nibuya, Morinobu, & Duman, 1995).
The main role of BDNF in stressful situations appears to be the pro-
tection against stress‐induced depressive symptoms (Autry, Adachi,
Cheng, & Monteggia, 2009). In the circulation, BDNF levels are often
reduced in individuals with a spectrum of stress‐related psychiatric
disorders such as mood and anxiety disorders (Fontenelle et al.,
2012; Grassi‐Oliveira, Stein, Lopes, Teixeira, & Bauer, 2008; Piccinni
et al., 2008; Viola et al., 2014). In healthy women, plasma‐BDNF levels
correlate positively with stress coping and resilience (Ma et al., 2016).
The objective of this study was to evaluate the effects of MBP on
behavioral and neuroendocrine indicators of stress in infertile women.
ET AL.
2 | METHODS
2.1 | Study approval and registration
This randomized controlled trial (RCT) was approved by the Research
Ethics Committee of Universidade Federal de Minas Gerais (Decision
Number 903.582) and registered at the Brazilian Clinical Trials Registry,
REBEC (Primary ID Number RBR‐7by76r) and Brazilian Ministry of
Health Human Research Registry (Protocol ID 35321414.0.0000.5149).
All patients included in this study signed an informed consent.
2.2 | Participants
The study population consisted of women aged 18–50 with the
diagnosis of infertility, defined as failure to become pregnant despite
regular sexual intercourse without contraceptive methods after 1 year
(Medicine, 2013; Zegers‐Hochschild et al., 2017). The main causes of
infertility in patients eligible for the study (n = 178) were male factor
(n = 38), anovulation (n = 19), tubal obstruction (n = 26), endometriosis
(n = 22), and unexplained infertility (n = 55). All participants were
scheduled to start an IVF cycle in the following 6 months at the repro-
ductive endocrinology unit of a teaching hospital in Belo Horizonte,
Southeast Brazil. The participants had been infertile for an average
of 7 years, had low‐to‐medium income, lived at the metropolitan
area of Belo Horizonte, and 91% were currently married or in
cohabiting union.
Participants were enrolled from October 2013 to April 2016, the
intervention period ranged from October 2013 to June 2016, and
the last follow‐up assessment was in June 2016.
2.3 | Randomization, allocation, and concealment
The eligible participants that agreed to be enrolled and signed the
informed consent were randomly assigned either to the intervention
group or the control group (Figure 1). The personnel involved in
participant enrollment received sequential opaque, sealed envelopes
containing the allocation group and was blinded to the envelop
contents. Randomization was performed through two computer
generated random number lists. The first 54 participants were
randomized without any restriction, which resulted in 35 allocations
to the intervention group and 19 to the control group. The remaining
124 participants were randomized prespecifying a 1:1 ratio between
groups.
The study was open label, but the outcomes were assessed by
self‐administered questionnaires or by biochemical assays performed
by personnel blinded to the participant treatment group.
2.4 | Intervention
The MBP intervention was administered to small groups who met for
2 hours weekly during 10 consecutive weeks. The intervention
comprised one introductory meeting, eight MBP sessions, and one
concluding meeting. The sessions included meditation, relaxation,
autogenic training, guided imagery, and biofeedback, as previously
described (Paiva et al., 2016; Saunders et al., 2007). These activities
are not specific to infertility, although the participants' concerns about
NERY ET AL.
FIGURE 1 Flow diagram showing the
selection, allocation, and follow‐up of the
participants
their infertility arise frequently (Paiva et al., 2016). The control group
attended the first and the last meetings but did not attend the MBP
sessions. The time interval between allocation and the first group
meeting ranged from 1 to 2 weeks.
2.5 | Outcome assessment
Participants were surveyed about stress and depressive symptoms,
general well‐being, hair cortisol levels, and serum BDNF levels at the
first and last meetings, that is, 1 week before starting and 1 week after
ending the MBP sessions. The questionnaires were self‐administered
at the hospital in both occasions.
2.6 | Primary outcome
2.6.1 | Stress symptoms
Stress symptoms were assessed with the Lipp's Stress Symptoms
Inventory (ISSL) that has been originally developed and validated in a
representative sample of Brazilian adults and subsequently used in
several clinical studies (Macedo & Diez‐Garcia, 2014; Solano et al.,
2016). The questionnaire was originally developed and validated in
Brazil, so translation was not required. The ISSL questionnaire is
divided in three parts, each one focusing on a specific period of time:
the previous 24 hours (12 physical and three psychological symptoms),
the previous week (10 physical and five psychological symptoms), and
the previous month (12 physical and 11 psychological symptoms). The
questions are self‐administered, and each item has a “yes” or “no”
response. It includes questions about autonomic symptoms (cold
extremities and tachycardia), eating disorders, sexual difficulties,
irritability, anxiety, tiredness, and others. In addition to quantifying
the symptoms, the instrument classifies the test result into five
sequential categories, named “no stress,” “alertness,” “resistance,” “near
3
exhaustion,” and “exhaustion,” according to the predominant
symptoms and their duration (Macedo & Diez‐Garcia, 2014).
2.7 | Secondary outcomes
2.7.1 | Depression
Participants were surveyed about depressive symptoms with the Beck
Depression Inventory (BDI), which has 21 items related to the
previous week, each one with four response options graded 0 to 3.
The overall score represents the sum of all items and ranges from 0
to 63. Higher scores reflect more depressive symptoms (Beck, Ward,
Mendelson, Mock, & Erbaugh, 1961; Gomes‐Oliveira, Gorenstein,
Lotufo Neto, Andrade, & Wang, 2012).
2.7.2 | General well‐being
We used the Psychological General Well Being Inventory (PGWBI)
that consists of 22 self‐administered items related to the previous
month, graded 1 to 6. The overall score represents the sum of all items
and ranges from 22 to 132. Higher values indicate greater well‐being
(Lundgren‐Nilsson, Jonsdottir, Ahlborg, & Tennant, 2013). This inven-
tory may also be used to assess quality of life (Petta et al., 2005).
2.7.3 | Hair cortisol
Hair cortisol was measured in a subset of participants (n = 16) who did
not use hair chemicals or frequent shampooing in the last 60 days,
which could affect hair cortisol levels (Hoffman, Karban, Benitez,
Goodteacher, & Laudenslager, 2014). Hair sampling and cortisol
extraction were performed as previously validated (Sauve, Koren,
Walsh, Tokmakejian, & Van Uum, 2007; Veldhorst et al., 2014). A tuft
of approximately 100 strands of hair was cut in the region of the scalp
apex as close as possible to the scalp and stored in aluminum foil at
room temperature. For cortisol extraction, 2 cm of the proximal
4 NERY
portion of each hair sample were cut into powder with a surgical
scissor, then 10‐mg hair powder were diluted in 1‐ml methanol and
incubated for 16 hr at 52°C. The supernatant was transferred to a
fresh glass tube and incubated at 52°C to evaporate until the sample
became completely dry (~24 hr). Dried samples were suspended in
100 μl of phosphate‐buffered saline (PBS) to be assayed.
Cortisol levels were measured in duplicate using a commercial
ELISA kit (Alpco Diagnostics, Windham, New Hampshire), following
the manufacturer's instructions. Reagents were prepared altogether
right before the assay, and a face mask was worn by the assay
performer to avoid saliva contamination of the test samples. Fifty
microlitres of each calibrator, control, and sample and 100 μl of the
conjugated working solution were incubated for 45 minutes at room
temperature on a plate shaker (200 rpm) and then washed three times
with 200 μl of diluted wash buffer per well using an auto washer. The
reaction was revealed with tetramethylbenzidine (TMB) substrate, and
the optical density was read at 450 nm. The cross‐reactivity of other
steroids with the kit antibodies did not exceed 13.6% (prednisolone,
13.6%; corticosterone, 7.6%; deoxycorticosterone and progesterone,
7.2%; cortisone, 6.2%; deoxycortisol and prednisone, 5.6%; dexameth-
asone, 1.6%). All samples were run in the same plate with 8%
intraassay coefficient of variation.
2.7.4 | Serum BDNF
Five millilitres of blood were collected between 07:00 and 10:00 a.m.
by venipuncture and centrifuged at 1,000 rpm during 20 minutes. The
supernatant (serum) was transferred to a cryotube and stored at
−80°C until the assay. BDNF was measured using the Human/Mouse
BDNF DuoSet ELISA kit (code DY248, R&D Systems, Minneapolis,
Minnesota), following the kit protocol. Serum samples were thawed
on the bench until achieving room temperature and homogenized.
The reagents were prepared altogether right before the assay. The
capture antibody was diluted in PBS, and the plate was coated with
100 μl of the diluted capture antibody and incubated overnight at
room temperature. Afterwards, the plate was washed three times with
400 μl of wash buffer using an auto washer. Then 30 μl of reagent
diluent were added into each well. The plate was incubated at room
temperature for 1 hour, the wash step was repeated, and 100 μl of
each sample or standard were added. After incubation for 2 hours at
room temperature, the wash step was repeated and 100 μl of the
detection antibody were added. After 2 hours at room temperature,
the plate was washed, 100 μl of Streptavidin‐HRP were added, and
after 20 minutes at room temperature, the reaction was stopped,
and the optical density was read at 450 nm (Fontenelle et al., 2012).
2.8 | Sample size
Sample size calculation was performed during the study planning
based on the primary outcome (Supporting Information). At least 31
participants per group were needed to detect a minimum difference
of three positive symptoms in the ISSL between the two groups or
between the two measures (pre and post) of each group with 90%
statistical power at 95% confidence level. Because the planned
analysis could not be performed without follow‐up data, the study
ET AL.
was ended only when the required number of participants had
attended the follow‐up visit.
2.9 | Statistical analysis
The results of the study were analyzed by the modified intent‐to‐treat
principle, which includes all subjects randomized and successfully
followed regardless of adherence to treatment (Del Re, Maisel,
Blodgett, & Finney, 2013). Data distribution were evaluated with the
D'Agostino & Pearson normality test. Baseline characteristics were
compared using Mann–Whitney test (or Kruskal–Wallis analysis of
variance [ANOVA] with Dunn's test) for quantitative variables and
chi‐square test with continuity (Yates) correction or Fisher's exact test,
as appropriate, for categorical variables. The effects of MBP or no
intervention on the outcome variables were evaluated by repeated
measures ANOVA with Time × Group interaction. We used Prism
Graphpad version 6 and SPSS version 22 software packages. All tests
were two‐tailed and p < 0.05 was considered statistically significant.
3 | RESULTS
3.1 | Participant flow
A total of 178 women were evaluated and considered eligible for the
study (Figure 1). All eligible participants were randomized, 97 were
assigned to receive the MBP intervention, and 81 were assigned to
the control group. From the MBP group, eight participants did not
receive the allocated intervention, 25 discontinued the intervention,
and 35 were lost to follow‐up. From the control group, 44 women
were lost to follow‐up. In the end, 62 participants from the MBP
group and 37 from the control group returned to follow‐up and were
available for analysis (Figure 1). Seven women underwent an IVF cycle
during the study period, and two of them (both from the MPB group)
returned to the study follow‐up. Of those, one had a positive and the
other had a negative biochemical pregnancy test.
3.2 | Baseline characteristics
The study groups were similar in all demographic and clinical charac-
teristics either comparing the participants that returned to follow‐up
(Table 1) or comparing all randomized subjects (Table S1). Further-
more, the two groups had no differences in baseline stress symptoms
(Figure 2), depressive symptoms (Figure 3), general well‐being
(Figure 4), hair cortisol (Figure 5b), or serum BDNF levels (Figure 5d).
3.3 | Primary outcome: Stress symptoms
Stress symptoms were analyzed before and after intervention in both
groups. The number of recent symptoms (last 24 hours) decreased in
the overall analysis (p < 0.01) but the effect of time did not differ sig-
nificantly between the two groups ( F = 0.039 for Time × Group inter-
action, p = 0.894, Figure 2a). However, MBP resulted in significant
decrease of stress symptoms in the past week ( F = 11.4 for
Time × Group interaction, p = 0.001, Figure 2b) and in the past month
( F = 14.6 for Time × Group interaction, p < 0.001, Figure 2c). In
NERY ET AL. 5

TABLE 1 Demographic and clinical baseline data of the two study

groups

Control MBP
Variable (n = 37) (n = 62) p value

Age (years) 37.0 ± 6.5 37.4 ± 5.3 0.530

BMI (kg/m2) 30.8 ± 5.7 29.8 ± 5.2 0.544
Primary female infertility 11/28 (39%) 33/56 (59%) 0.142
Length of infertility (years) 9.1 ± 5.2 7.5 ± 3.8 0.621
Education
FIGURE 3 (a) Depressive symptoms with mindfulness‐based
Elementary 6/35 (17%) 5/58 (9%) 0.346
program versus no intervention (control). The box plots represent
High school 18/35 (51%) 28/58 (48%)
the quartiles, and the error bars represent the 10th and 90th centiles
College 11/35 (31%) 25/58 (43%) of the Beck Depression Inventory (BDI) scores, and the p value refers
Physical activity 14/31 (45%) 35/54 (65%) 0.124 to repeated measures ANOVA. (b) Variation (post minus pre) of BDI
Smoking 2/33 (6%) 0/54 (0%) 0.141 scores. p value refers to Mann–Whitney test for independent samples
Alcohol drinking 10/36 (28%) 19/59 (32%) 0.822
Use of antidepressant drug 3/26 (12%) 9/48 (19%) 0.522
Stress stage (ISSL classification)
No Stress 13/35 (37%) 23/60 (38%) 0.686
Alertness 0/35 (0%) 1/60 (2%)
Resistance 14/35 (40%) 27/60 (45%)
Near exhaustion 8/35 (23%) 8/60 (13%)
Exhaustion 0/35 (0%) 1/60 (2%)

Note. This table includes only the participants that returned to follow‐up.
Quantitative variables are expressed as means ± standard deviation. Cate-
gorical variables are expressed as a percentage of the participants with that
variable available.
particular, the median number of symptoms of chronic stress per-
ceived in the past month decreased from six (interquartile range 2 to
9) before the MBP to two (interquartile range 1 to 4) after the inter-
vention. Conversely, the control group had no significant change in
stress symptoms between the first and the second assessment
(Figure 2).
3.4 | Secondary outcomes: Depression, general well‐
being, hair cortisol, and serum BDNF
Depressive symptoms subsided only in the MBP group, with a 45%
decrease in the median BDI score (Figure 3). In contrast, the control
FIGURE 4 (a) General well‐being with mindfulness‐based program
versus no intervention (control). The box plots represent the
quartiles, and the error bars represent the 10th and 90th centiles of
the Psychological General Well Being Inventory (PGWBI) scores, and
the p value refers to repeated measures ANOVA. (b) Variation (post
minus pre) of PGWBI scores. p value refers to Mann–Whitney test for
independent samples
group had no significant change in depressive symptoms between
the first and the second evaluation.
At the same time, the MBP group had significant improvement in
general well‐being (Figure 4). The PGWBI score increased by approxi-
mately 19% in the MBP group, contrasting with no significant change
in the control group.
As shown in Figure 5, hair cortisol levels at baseline were higher
among women with symptoms of chronic stress in the “resistance”

FIGURE 2 Stress symptoms with mindfulness‐based program versus no intervention (control). The box plots represent the quartiles, and the
error bars represent the 10th and 90th centiles of the number of positive symptoms in the previous 24 hours (a), week (b), or month (c). Each
time period has a specific list of physical and psychological symptoms that are checked by the respondent as being present or absent. p values
refer to repeated measures ANOVA
6 NERY
stage, whereas serum BDNF levels did not vary according to the stress
category. In addition, hair cortisol and serum BDNF levels did not
change significantly after MBP or no intervention (control). These
results remained unchanged after sensitivity analyses excluding
women with endometriosis (Rocha et al., 2017) or using antidepres-
sant drugs (Zhou et al., 2017), which could have affected serum BDNF
levels (data not shown).
4 | DISCUSSION
The findings of the current RCT suggest that an MBP may be effective
in reducing self‐reported stress symptoms as well as depressive symp-
toms while improving general well‐being in infertile women.
The population of this study has many potential psychological
sources of stress. The mean age was 37 years, and the length of
infertility was more than 7 years, which means a long process of
expectation and frustration together with an increasing pressure
imposed by the advancing age and the consequent reduction in
treatment success rates (Hourvitz et al., 2009). These women might
further be stressed by insufficient emotional support from their
partners and relatives and/or by financial instability as fertility drugs
are very expensive and not covered by health insurance in Brazil
(Paiva et al., 2016). Moreover, the prevalence of depressive and
anxiety disorders in women before a new course of assisted
reproductive technology may be as high as 40% (Chen, Chang, Tsai,
& Juang, 2004).
Our results show the efficacy of an eight‐session MBP to reduce
self‐reported stress symptoms. The first studies about the effective-
ness of mindfulness were conducted by Kabat‐Zinn more than three
decades ago (Kabat‐Zinn, 1982). A review by Holzel et al. (2011)
identified some key mechanisms through which mindfulness can affect
health, such as attention regulation, body consciousness, emotional
ET AL.
FIGURE 5 Hair cortisol (a,b) and serum
BDNF (c,d) levels. Basal levels (a,c) were
analyzed according to the categorization of
participants by the stress questionnaire into
“no stress” or different stages of chronic
stress, namely, “resistance” and “near
exhaustion.” The categories “alertness” and
“exhaustion” had only one participant each
and therefore were not analyzed. *p < 0.05
versus “no stress” (Kruskal–Wallis ANOVA
followed by Dunn's test). There was no
significant change in either biomarker (b,d)
after mindfulness‐based program or no
intervention (control; repeated measures
ANOVA)
regulation by increase in positive reappraisal and non‐reactivity to
inner experiences, and change of perspective of the self. Functional
neuroimaging studies described that the most relevant cerebral areas
activated by mindfulness practices are the insula, related to body
awareness, several areas of the prefrontal cortex, related to the regu-
lation of emotions, and the anterior cingulate cortex, related to atten-
tion (Holzel et al., 2011; Paul, Stanton, Greeson, Smoski, & Wang,
2013; Smith et al., 2018). Although different people have different
self‐coping strategies (Daubenmier, Hayden, Chang, & Epel, 2014),
the MBP techniques are focused on training the participants to
establish a new perspective of self‐emotions with curiosity and no
judgment (Paiva et al., 2016). These techniques are directly related
to stress reduction by helping the development of the ability called
“capacity of re‐evaluation,” which is the individual capacity to turn
stressful events into beneficial events, giving a new significance and
perspective to suffering (Holzel et al., 2011).
Depression is a common mental disorder and an important
contributor to the overall global burden of disease. It is the main cause
of disability worldwide, affecting more women than men (Hasin et al.,
2018; Kessler, 2003). Therefore, the amelioration of depressive
symptoms after engaging in the MBP was an important finding of
the present study. This benefit is possibly related to some abilities
acquired through MBP techniques, such as development of
decentering capacity (Galhardo, Cunha, & Pinto‐Gouveia, 2013;
Hayes‐Skelton & Graham, 2013) and reduction of cognitive reactivity
(Raes, Dewulf, Van Heeringen, & Williams, 2009).
The current study also found that the participants of MBP had an
increase in general well‐being. This result corroborates with previous
studies that demonstrated improvements in quality of life after MBP
(Henderson et al., 2012; Li et al., 2016; Paiva et al., 2016; Stefanaki
et al., 2015). Depression is one of the main predictors of well‐being
perception and quality of life (Scalzo, Kummer, Cardoso, & Teixeira,
2009); therefore, it is not surprising that the reduction of depressive
NERY ET AL.
symptoms after the MBP was accompanied by an improvement in
general well‐being.
Cortisol is secreted by the adrenal glands in response to chronic
stress as a consequence of hypothalamic‐pituitary‐adrenal activation.
We expected a reduction of hair cortisol levels after MBP interven-
tion, which did not occur. Although stress symptoms and hair cortisol
were measured concurrently, these two parameters have different
assessment periods as hair samples were long enough to span approx-
imately 60 days of cortisol accumulation, whereas the stress symptom
inventory went back to the last 30 days. Maybe more time would be
necessary between the end of intervention period and hair collection
to detect a reduction on cortisol. In addition, mild changes in hair
cortisol might not have been noted due to lack of statistical power,
as we measured cortisol in only a small subset of study participants
to avoid the interference of hair chemicals.
BDNF is related to stress response and coping (Herman et al.,
1989; Jacobson & Sapolsky, 1991; Nibuya et al., 1995; Young,
Haskett, Murphy‐Weinberg, Watson, & Akil, 1991). Here we tested
whether serum BDNF levels would be affected by the MBP, and we
found no change of serum BDNF levels 1 week after concluding the
MBP compared with 1 week before starting it. It is noteworthy that
serum BDNF levels at baseline were unrelated to stress category in
our study population. Similarly, a recent study with cyclists detected
acute BDNF release during exercise and showed that intensified train-
ing improved the athletes' mood state, however, without modifying
their plasma BDNF levels (Piacentini et al., 2016). The time latency
for serum BDNF changes in response to behavioral and cognitive
interventions is not clear‐cut and probably varies according to the
health condition of the individual and the type of therapy
(Hakansson et al., 2017; Kobayashi et al., 2005; Sanada et al., 2016;
Turakitwanakan, Mekseepralard, & Busarakumtragul, 2015; Yamada,
Yoshimura, Nakajima, & Nagata, 2012).
A recent Cochrane review concluded that the effects of psycho-
logical and educational interventions on mental health of infertile
women are uncertain due to the low quality of the existing evidence
(Verkuijlen et al., 2016). In fact, only observational studies, non‐
randomized trials, or small RCTs with high risk of bias have evaluated
such interventions in the specific group of subfertile people (Feili et al.,
2012; Galhardo et al., 2013; Li et al., 2016; Pascoe et al., 2017;
Shahrestani et al., 2012). Accordingly, the main methodological
strengths of the present study are the RCT design with true random-
ization, the adequate statistical power of the analyzed sample, the
blinding of personnel involved in allocation and outcome assessment,
and the modified intention‐to‐treat analysis.
Nonetheless, the study has some limitations. Performance bias
cannot be ruled out because the intrinsic characteristics of the MBP
do not permit blinding of the participants. However, this risk is partly
mitigated by the use of objective questionnaires that focus on the
presence or absence of symptoms rather than perceived distress.
We must also recognize the risk of attrition bias because 44% of the
randomized participants were lost to follow‐up. However, the baseline
characteristics of the MBP and control groups were similar when we
compared only the remaining participants that were fully assessed.
Attrition bias may affect the results when the main reason for dropout
is some variable that also influences the outcome. In this study, it may
7
be argued that the participants that perceived a greater benefit of the
MBP were more likely to remain in the program and return to
follow‐up, thereby leading us to overestimate the benefits of the
intervention. However, the same phenomenon would be expected to
happen in the control group, assuming that the participants who
remained in the study were more likely to be coping and resilient. In
addition, the control group had no significant improvement in the
stress or depressive symptoms despite having more participants lost
to follow‐up.
The findings of the present trial agree with previous evidence
showing benefits of behavioral and cognitive therapies to reduce
stress and improve quality of life, but they should be extrapolated with
caution considering the peculiarities of the study population. MBPs
are not substitutes for other therapeutic interventions and are better
used as complement to a therapeutic plan. Mindfulness‐based
therapies act on symptoms and mechanisms shared by many health
conditions and the understanding of such mechanisms will help the
refinement of MBPs to act on more specific physiological and psycho-
logical targets, hopefully with better results (Malinowski, 2013).
Further studies are also needed to evaluate the effect of MBP on
infertile men, because some aspects of the psychological response to
infertility may be gender‐specific (Martins et al., 2016).
On the basis of our results, we conclude that in women undergo-
ing infertility treatment the participation in an MBP can reduce self‐
reported stress symptoms (physical and psychological), reduce
depressive symptoms, and improve general well‐being.
ACKNOWLEDGMENT
We thank the psychologist Márcia A. Fonseca, PhD, for her expert
advice during the study. Research supported by Conselho Nacional
de Desenvolvimento Científico e Tecnológico (CNPq) through the
National Institute of Hormones and Women's Health (Grant
465482/2014‐7).
CONFLIC T OF INT E RE ST
The authors have declared that they have no conflict of interest.
ORCID
Fernando M. Reis http://orcid.org/0000-0002-9258-7472
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SUPPORTI NG INFORMATION
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How to cite this article: Nery SF, Paiva SPC, Vieira ÉL, et al.
Mindfulness‐based program for stress reduction in infertile
women: Randomized controlled trial. Stress and Health.
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