Human Reproduction, Vol.30, No.12 pp.

2764–2773, 2015
Advanced Access publication on October 13, 2015 doi:10.1093/humrep/dev248

ORIGINAL ARTICLE Early pregnancy

A RCT of psychotherapy in women with

nausea and vomiting of pregnancy
Mahbobeh Faramarzi 1, Shala Yazdani 2,*, and Shahnaz Barat 2

Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019

1
Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
2
Infertility and Reproductive Health Research Center, Health Research Institute, Obstetrics & Gynecology Department,
Babol University of Medical Science, Babol, Iran

*Correspondence address. Infertility and Reproductive Health Research Center, Health Research Institute, Obstetrics & Gynecology
Department, Ganjafroz street, Babol University of Medical Science, Babol 47745-47176, Iran. Tel: +98-9112142116; Fax: +98-1112229591;
E-mail: shahla_yazdani_1348@yahoo.com

Submitted on February 18, 2015; resubmitted on August 3, 2015; accepted on August 27, 2015

study question: Does adding psychological intervention to medical therapy improve nausea/vomiting, psychological symptoms, and
pregnancy distress in women with moderate nausea and vomiting of pregnancy (NVP)?
summary answer: Three weeks of medical therapy plus psychotherapy yielded statistically and clinically significant improvements in
NVP-specific symptoms, anxiety/depression symptoms, and pregnancy distress, compared with medical therapy alone.
what is known already: Pregnancy with nausea/vomiting is associated with psychiatric morbidity. Evidence supports the exploration
of psychosocial reactions in addition to biochemical markers related to NVP.
study design, size, duration: This prospective, open-label, randomized, controlled, parallel-group study was performed at two
obstetrics clinics in Iran. A total of 86 women, aged 18–40 years, between 6 and 12 weeks pregnant with moderate NVP, more than 5 years of edu-
cation, and not currently practicing any relaxation techniques or undergoing any psychotherapy, were enrolled from June 2013 to November 2014.
participants/materials, setting, methods: A total of 86 moderate NVP women were randomly allocated to either a control
(medical therapy alone) or experimental (medical therapy plus psychotherapy) group. Block randomization was achieved using a paper list prepared
by an investigator with no clinical involvement in the trial. The experimental group was given pyridoxine hydrochloride (40 mg daily) for 3 weeks, and
also received intensive mindfulness-based cognitive therapy (MBCT) in eight individual sessions (50 min each) over 3 weeks. The control group was
given pyridoxine hydrochloride (40 mg daily tablet) for 3 weeks alone. All participants completed the Rhodes index of nausea, vomiting and retching
(RINVR), the hospital anxiety and depression scale (HADS), and the prenatal distress questionnaire (PDQ) at baseline, 3 weeks after baseline at the
end of the study, and at a 1 month post-treatment follow-up. Linear mixed-effects models were used, in an intention-to-treat analysis.
main results and role of chance: In the psychotherapy plus medical therapy group, the mean relative difference between baseline
and post-treatment decreased for RINVR; nausea 8.2 (95% confidence interval (CI) 4.1, 10.2), vomiting 3.5 (95% CI 1.5, 5.8), and total RINVR 11.7
(95% CI 6.5, 16.5), for HADS; anxiety 5.1 (95% CI 3.2, 9.2), depression 3.5 (95% CI 2.4, 7.3), total HADS 7.2 (95% CI 4.4, 12.1), for PDQ; birth
concerns 3.3 (95% CI 1.3, 9.1), body concerns 1.5 (95% CI 0.9, 5.1), relationship concerns 2.1 (95% CI 1.2, 5.9), and total PDQ 5.9 (95% CI
3.5, 10.6). At 1 month after treatment, the statistically significant improvement in RINVR, HADS and PDQ, as well as clinical improvement in severity
of symptoms, persisted. Medical therapy plus psychotherapy also improved nausea/vomiting symptoms, psychological symptoms, and reduced preg-
nancy distress more than medical therapy alone, with an effect size of 0.42–0.72 over the trial period.
limitations, reasons for caution: The conclusions were limited to a small number of women with moderate NVP. It is unclear
whether the difference between the outcomes in the different groups was related to MBCT alone, or to the extra time and attention paid to patients
in the medical therapy plus psychotherapy. The participants in the study did not remain blind to the treatment and the outcome may only be
representative of women with moderate NVP who have been referred to obstetrics clinics.
wider implications of the findings: These findings show that adding 3 weeks of psychological intervention to medical therapy may
appear to produce positive therapeutic outcomes upon conclusion of treatment, and 1 month after treatment. This suggests that psychotherapy
should be considered as an adjunctive treatment option for women with moderate NVP. In future studies, however, a group of patients who are
receiving placebo psychotherapy along with medical treatment should be included. Furthermore, an economic evaluation of the addition of psycho-
logical intervention to standard medical therapy would be useful.

& The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
Psychotherapy and nausea and vomiting of pregnancy
study funding/competing interest(s): The study was funded by Infertility and Reproductive Health Research Center of the
Babol University of Medical Sciences. The authors have no conflicting interests.
trial registration number: IRCT201304035931N2.
trial registration date: 3 April 2013.
date of first patient’s enrolment: 1 June 2013.
Key words: nausea / vomiting / pregnancy / mindfulness / depression / anxiety
Introduction
Nausea and vomiting of pregnancy (NVP) is a common medical condition
with the significant potential to compromise women’s well-being, even
when symptoms are moderate. Women with moderate NVP may be
just as likely to have a low quality of life score as women with severe
NVP. NVP not only affects the physical health of women, but also can
have a negative impact on family, and social and occupational functioning
(Munch et al., 2011). Furthermore, severe NVP has been documented to
have negative effects on the fetus, such as low birthweight and preterm
birth (Czeizel and Puhó, 2004).
The exact cause of NVP is unknown. However, both biological and
psychological theories have been implicated in the pathogenesis of NVP.
Although psychosocial theories about NVP have not been studied exten-
sively, there is growing evidence of a psychological etiology. Evidence sup-
ports the examination of psychosocial reactions in addition to exploring
biochemical markers related to NVP (Kuo et al., 2010). Psychoanalytic the-
ories describe NVP as a conversion or somatization disorder. This implies
that women with NVP are transforming psychological distress into physical
symptoms. Also, reactions to stress during pregnancy can clearly be
somatic and include nausea and vomiting (Buckwalter and Simpson, 2002).
NVP in early pregnancy is associated with psychiatric morbidity
(Swallow et al., 2004). A recent study reports that the severity of symp-
toms of NVP is associated with symptoms of major depression (Kramer
et al., 2013). Previous research demonstrates that women who experi-
ence severe NVP are significantly more likely to have a pre-existing psy-
chiatric illness (Roseboom et al., 2011). Evidence emphasizes that
women with severe NVP are more likely to suffer from any mood,
anxiety or personality disorder (Uguz et al., 2012). However, it is not
more likely for a woman with severe NVP to have a personality disorder
or psychological disorder than a woman suffering from mild to moderate
NVP (D’Orazio et al., 2011). Psychosocial variables, such as living alone
and working, have a clear influence on nausea and vomiting during preg-
nancy (Markl et al., 2008). In women with NVP, maternal psychosocial
adaptation may be explained by the severity of nausea and vomiting, per-
ceived stress, and social support (Chou et al., 2008).
Optimal treatment of NVP remains a major challenge. The symptom-
atic improvement of patients with NVP after pharmacological interven-
tions remains controversial. Matthews et al. (2010) reviewed the
effectiveness and safety of all interventions for NVP and conclude that
there is insufficient strong evidence to support any particular interven-
tion. Little research is available regarding the role of psychotherapy in
NVP patients. Madrid et al. (2011) report four cases of women with
NVP who were treated with a brief form of hypnosis. Other studies
suggest medical hypnosis to be a well-documented alternative treatment
for severe NVP (Simon and Schwartz, 1999).
2765
Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019
Mindfulness-based cognitive therapy (MBCT) is a psychotherapy
program developed by Segal et al. (2002). MBCT combines cognitive
therapy exercises with mindfulness skills. This combination is believed to
enable individuals to increase their awareness and facilitate early recognition
of any unhelpful thinking patterns. MBCT consists of accepting thoughts and
feelings without judgment. The aim of MBCT is freedom from the tendency
to get drawn into automatic reactions to thoughts, feelings and events (Segal
et al., 2002). The program involves teaching individuals various stress
management, relaxation, self-care and self-help techniques in a systematic
way. The core skill taught is mindfulness, which uses meditation practice
to increase attention and awareness (Baer, 2003).
To date no randomized, controlled, prospective trial assessing the effect-
iveness of MBCT psychotherapy in patients with NVP has been published. In
the present study, we compared the outcome of medical therapy plus
MBCT psychotherapy and medical therapy with the outcome of medical
therapy alone in patients with moderate NVP. The effects of MBCT psycho-
therapy on NVP symptoms, depression and anxiety symptoms, and
pregnancy stress were investigated.
Materials and Methods
The trial is registered at the Iranian Registry of Clinical Trials, number
IRCT201304035931N2. The patients were recruited from the obstetrics
clinics of two teaching hospitals at Babol University of Medical Sciences
(Babol, Northern Iran) from June 2013 to November 2014. The case
notes of all the clinic patients were screened by a researcher associated
with the study to determine recruitment eligibility. Subjects were considered
to have NVP if they sought treatment for the symptoms of nausea and vomit-
ing at 6 – 12 weeks of their pregnancy without having received any treatment
earlier for the same. Eligible women who were more than 18 years old with
more than 5 years’ education were invited to enter the study.
We classified patients in three groups based on the severity of their NVP,
which was diagnosed using the Rhodes index of nausea, vomiting and retching
(RINVR): vomiting and retching 1 – 8 (mild), 9 – 24 (moderate), and 24 – 32
(severe). Those with a score of mild or severe NVP (≤8 or ≥24 on the
RINVR) were excluded from the study. Only patients with moderate NVP
were eligible to enter.
Women currently practicing any relaxation techniques or undergoing any
psychotherapy were also ineligible. Patients were also excluded from the
study if they were beyond 12 weeks of gestation, had hyperemesis
gravidarum, multiple gestation, gestational trophoblastic disease, thyroid
disease, ovarian cyst, gastroesophageal reflux disease or other forms of
acid peptic disorder, psychiatric illness, any other acute confounding illness
that could cause nausea or vomiting, or taking medication other than that
permitted by the study protocol. Women who had any medical indication
for termination of pregnancy during the gestational age of 6 – 12 weeks
(for example major fetal malformation, advanced medical complications)
were also excluded.
2766
After assessing the inclusion criteria (NVP symptoms, age, gestational age,
education, psychotherapy), completing the demographic questionnaire and
the RINVR, the patients were referred to two obstetricians to evaluate
and confirm their NVP diagnosis. Of 124 eligible women, 109 patients
were accepted to enter the study and were referred to the obstetricians.
Obstetric ultrasonography confirmed singleton intrauterine pregnancy in
all cases. Physical, biochemical and ultrasonographic examinations were
performed to exclude severe forms of nausea and vomiting necessitating
admission to hospital (hyperemesis gravidarum).
Eighty-six patients diagnosed with moderate NVP (RINVR score 9 – 24)
agreed to participate in the study. Figure 1 shows the flow diagram of parti-
cipants through each stage of the RCT.
The randomization method, prepared in advance by a statistician, allocated
the participants to either the control or experimental group in a 1:1 ratio in
blocks of 4, according to a paper list-generated random assignment sequence
stratified by hospital site. The randomization and paper list process was under-
taken by a nurse who was not involved in evaluating the participants, in order to
maintain concealment. Only the nurse had access to the paper list, which was
kept in one of the teaching hospitals until the end of the study. Serial evaluations
of patients’ symptoms were performed, by a midwife who was blind to the
treatment status of the patients, using three questionnaires at three time
points: at the beginning of the study (baseline), at post-treatment (3 weeks
after baseline), and at follow-up (7 weeks after baseline).
Patients in the control group received medical treatment alone while those
in the experimental group received medical treatment plus psychotherapy
(see Table I). In the beginning of the study, all of the participants were
asked to complete the RINVR, the hospital anxiety and depression scale
(HADS), and the prenatal distress questionnaire (PDQ). Demographic char-
acteristics such as age, educational level, marital status and the duration of
their NVP symptoms were ascertained at baseline.
All patients gave their informed consent. All aspects of this protocol were
approved by the Medical Ethics Committee of Babol University of Medical
Sciences.
Outcome measures
To evaluate NVP-related health outcomes, a disease-specific questionnaire
was used. Primary outcome was evaluated using the RINVR. To evaluate
psychological status, two questionnaires were used. Secondary outcome
was measured according to the number and intensity of responses to the
PDQ, and changes regarding emotional distress, using the HADS.
RINVR
The RINVR is a patient self-report instrument that assesses both the object-
ive and subjective factors of nausea and vomiting. This simple, reliable and
validated instrument consists of eight 5-point, self-report items (Kim et al.,
2007). Scores can range from 0 to 32. Classification of the nausea, vomiting,
and retching score involves: 0 (none), 1 – 8 (mild), 9 – 24 (moderate), and 24 –
32 (severe). Cronbach’s alpha of nausea, vomiting, retching, and total experi-
ence scores on the RINVR ranged from 0.912 to 0.968. Coefficients of con-
struct validity for nausea components and emetic components of the RINVR
were 0.860 – 0.928 and 0.724– 0.811, respectively. Test-retest scores of all
items strongly correlated and highly agreed.
PDQ
The PDQ was designed by Yali and Lobel (1999) to assess pregnancy-specific
stress (maternal fears and worries related to pregnancy). The PDQ is a
12-item scale that provides three subscales: concerns about birth and the
baby, concerns about weight/body image, and concerns about emotions
and relationships. Each item is rated on a 5-point Likert scale ranging from
0 (not at all) to 4 (extremely). PDQ has a possible range of 0 –48 for a
total score, 0 –24 for birth concerns, and 0 – 12 for both body concerns
Faramarzi et al.
and relationship concerns. There is no cutoff point for PDQ scores to indicate
the severity of pregnancy distress. However, higher scores indicate severe
pregnancy-specific distress.
The PDQ is a reliable and valid measure of pregnancy-specific stress and is
widely used in obstetrics research (Yali and Lobel, 1999; Gennaro et al., 2008).
The internal consistency of the PDQ is high (Cronbach’s alpha ¼ 0.81)
(Yali and Lobel, 1999).
HADS
The HADS is a 14-item measure with four possible answer choices to each
stem. Each answer is scored 0–3. It comprises two subscales for anxiety and
Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019
depression symptoms. Each item can be interpreted in ranges of anxiety and
depression: normal (0–7), mild (8–10), moderate (11–14) and severe
(15–21). The HADS has been validated as a useful tool with which to identify
anxiety and depression cases in antenatal patients (Abiodun, 1994). It has
been validated and adapted for an Iranian population (Cronbach’s alpha:
0.78 for the HADS anxiety subscale and 0.86 for the HADS depression
subscale) (Montazeri et al., 2003).
Clinical intervention
Medical treatment
All patients with NVP (in both the experimental and control groups) were given
pyridoxine hydrochloride (40 mg tablet daily) for 3 weeks. Previous RCTs
report that pyridoxine significantly reduces the severity of NVP symptoms in
women with moderate or severe nausea and vomiting (Vutyavanich et al.,
1995; Tan et al., 2009; Wibowo et al., 2012; Babaei and Haji Foghaha, 2014).
Psychological treatment
Patients with NVP allocated to the psychotherapy group received intensive
MBCT: Eight individual sessions (50 min each) over 3 weeks. The 3-week
period for both interventions (medical and psychological) took into consid-
eration that the mean duration of NVP is short (6 weeks). A recent
meta-analysis provides evidence that brief psychotherapies, such as cognitive
behavioral therapy (CBT) and problem-solving therapy, are an effective treat-
ment within primary care (Cape et al., 2010).
A female MBCT psychotherapist, experienced in MBCT methods who had
been working with the obstetrics departments for several years, conducted
the psychotherapy sessions. Intensive MBCT for patients with NVP consisted
of integrating elements of mindfulness-based stress reduction (MBSR) and
CBT with guided eating meditations.
The program drew on traditional mindfulness meditation techniques, as
well as guided meditation, to address specific issues pertaining to eating-
related self-regulatory processes. The meditative process is integrated into
daily activity related to eating. Mindfulness meditation is conceptualized as
a way of training attention to help individuals, first to increase the awareness
of automatic patterns, and then to disengage undesirable reactivity. It is also
viewed as a way to heighten awareness of potentially more healthy aspects of
functioning, and to use such awareness to more ‘wisely’ inform behavior and
experience (Kristeller, 2003).
As outlined in Table I, each session incorporated meditation practice.
General sitting meditation is similar to practices used in MBSR and MBCT.
MBSR was developed by Jon Kabat-Zinn (1990) for coping with stress. The
MBCT program largely involves mindfulness-based ‘mini-meditations’
which teach participants to stop for a few moments at key times during
daily activities, particularly meal and snack times, to practice nonjudgmental
awareness of thoughts and feelings. Several eating-related guided meditations
were included, in which participants focus nonjudgmental attention on sensa-
tions, thoughts, and emotions related to nausea/vomiting triggers. A number
of the eating-related meditations used food, beginning with the raisin medi-
tation and moving toward more complex and challenging foods, culminating
with making food choices mindfully; first between just two foods and then
Psychotherapy and nausea and vomiting of pregnancy
Figure 1 Flow chart for two randomized groups.
between food at a buffet. Several sessions also incorporated mindfulness
body work, moving from a body scan to self-soothing touch, then mindful
walking. The intervention then made a transition to a forgiveness meditation
related to one’s own body and self, and a wisdom meditation to develop
better choice- and decision-making techniques.
Statistical analyses
As this study is the first RCT comparing MBCT plus medical therapy with
medical treatment alone in the treatment of moderate NVP, we did not
have enough information from previous studies to calculate an appropriate
sample size. Therefore, before starting the project, we conducted a pilot
2767
Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019
study in order to help calculate the sample size. The mean reduction of
RINVR scores in the two groups of psychotherapy plus medical therapy
and medical treatment alone was 5.5 (SD ¼ 2.7) and 3.9 (SD ¼ 1.5), re-
spectively. Thus, the required sample size with a significance level of 5%,
power of 90%, and attrition rate of 10% was calculated to be 43 in each
group.
The characteristics of the two subject groups were described using mean
and SD frequencies and percentages. Baseline differences between the two
groups were tested using the Student’s t-test for continuous data, and the
Chi-square for categorical data.
The results were analyzed using a mixed-effects model with a fixed-effects
approach. The mixed-effects (regression) model has important advantages
2768 Faramarzi et al.

Table I Outline of sessions for the intensive mindfulness-based cognitive therapy group.

Session 1: Building a rapport with, and obtaining information from the client; identifying automatic thoughts; introduction to self-regulation model: raisin
exercise; introduction to mindfulness meditation with in-session practice. Assignment: Meditate with tape (continued throughout trial period).
Session 2: Helping the client to recognize that thoughts are not facts, teaching use of the thought record, educating the client about cognitive distortion. Brief
meditation (continued in each session); mindful eating exercise (cheese and crackers); concept of mindful eating; body scan. Assignment: Eat 1 snack or meal
per day mindfully (continued throughout the remainder of the trial period with increasing number of meals/snacks).
Session 3: Education of diaphragmatic breathing and sleep hygiene. Mindful eating exercise (sweet, high-fat food). Assignment: Mini-meditation before meals.
Session 4: Teaching mindful eating and mindful labeling of thoughts, feelings,
and behaviors, enhancing recognition of personal consequences of chronic worry, conducting a cost-benefit analysis of the client’s chronic worry. Forgiveness

Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019

meditation. Assignment: Eat all meals and snacks mindfully.
Session 5: Image nausea/vomiting meditation; seated yoga; wisdom meditation; walking meditation. Assignment: Attend to taste and satisfaction/enjoyment,
eat all meals and snacks mindfully.
Session 6: Generating a hierarchy of worries, imaginary exposure with acceptance, incorporating in vivo exposure through increased participation in planned events.
Session 7: Generating a hierarchy of birth concerns, body concerns, and relationship concerns, imaginary exposure with acceptance, incorporating in vivo
exposure through increased participation in planned events of pregnancy and delivery.
Session 8: Review of progress, reviewing the insights and techniques found most useful by the client, identifying obstacles to practice, individual evaluation of
the sessions.

over a repeated-measurement analysis of variance. The mixed-effects

(regression) model uses all available data on each subject, it is unaffected Table II Demographic characteristics of the patients in
by randomly missing data, it can flexibly model time effects, and it allows a RCT of psychotherapy in women with nausea and
the use of realistic yet parsimonious variance and correlation patterns for vomiting of pregnancy.
particular applications. The mixed-effect model takes into account all avail-
able data from all randomized participants, making it a full intention-to-treat Medical therapy plus Medical therapy
analysis (Gueorguieva and Krystal, 2004). psychotherapy alone
To examine the effect of intensive MBCT on the course of NVP symptoms, (n 5 43) (n 5 43)
........................................................................................
we used a mixed-effects model with time, treatment, and time × treatment Age (years); mean (SD) 25.11 (4.60) 23.27 (5.24)
interaction. By using this model, we considered three times (baseline, post-
Gestational age (weeks); 7.69 (1.88) 7.74 (1.27)
treatment and follow-up) as a repeated factor and group (psychotherapy
mean (SD)
and control) as a fixed factor. This model was used for all the dependent vari-
ables to assess whether the interaction effect time × group was significant. For Level of education, N (%)
each group of trials, mixed-effects models, with three times (baseline, post- Primary/high school 36 (83.7) 32 (74.4)
treatment and follow-up) as the fixed factor, were used to determine the University 7 (16.3) 11 (25.6)
change-dependent variables during three series measurements. Bonferroni Gravidity, N (%)
tests were conducted to explore pairwise comparisons at each time of admin- 1 17 (39.5) 22 (51.2)
istration. A Bonferroni correction to the level of significance was applied, 0.013
2– 3 25 (58.2) 2 (46.6)
(0.05/4). All of the statistical analyses were performed using the Statistical
Package for the Social Sciences software, version 19 (SSPS, Inc., Chicago, IL, .3 1 (2.3) 1 (2.3)
USA) and ,0.01 was regarded as statistically significant. Time with NVP, N (%)
To measure the responsiveness of treatment, the subjective clinical 1– 2 weeks 35 (81.4) 34 (79.1)
improvement of general and disease-specific health after treatment and follow- ,2 weeks 8 (18.6) 9 (20.9)
up was compared in both the experimental and control groups by means of the
Chi-square test. NVP, nausea and vomiting of pregnancy.

Results
Table II shows the characteristics of the study sample. The experimental
and control groups were well matched with respect to baseline charac-
teristics. There were no statistically significant differences between the
two groups in age, gestational age, gravidity, highest educational level
and the duration of NVP symptoms.
Nausea and vomiting symptoms
Table III shows the trend of changes in the mean scores of nausea
and vomiting symptoms in the two groups over the trial period. The
mixed-effects model analysis of the RINVR subscales revealed a
significant interaction effect for group × time for all of the NVP symp-
toms. There were differences between the medical therapy plus psycho-
therapy and medical therapy alone groups in terms of the improvement
of all NVP symptoms over the trial period: nausea symptoms, vomiting
symptoms and total RINVR scores (P , 0.001). The mixed-effects
model analysis conducted on each group over the time of the trial
revealed that the mean scores of NVP symptoms improved significantly
in the medical therapy plus psychotherapy group from pretreatment
through to post-treatment and follow-up (P , 0.01). The mean differ-
ence between baseline and post-treatment decreased for nausea 8.2
(95% CI, 4.1, 10.2), vomiting 3.5 (95% CI, 1.5, 5.8) and total RINVR
11.7 (95% CI, 6.5, 16.5). Medical therapy alone also improved NVP
 Psychotherapy and nausea and vomiting of pregnancy
Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019
Table III Mean scores of nausea/vomiting and psychological symptoms in experimental and control groups over the trial period.

Scales Baseline Mean score Effect size

........................................................ ......................................................................................................... ..................................................
Medical therapy plus Medical therapy Post-treatment Follow-up Post-treatment Follow-up
psychotherapy alone .................................................. ................................................... versus baseline versus baseline
Mean (SD) Mean (SD) Experiment Control P-value Experiment Control P-value
Mean (SD) Mean (SD) Mean (SD) Mean (SD)
..........................................................................................................................................................................................................................................................
RINVR
Nausea symptoms 13.81 (3.44) 14.37 (3.51) 5.62 (4.33)a 7.66 (0.71)a 0.004 5.52 (3.43)a 7.11 (5.74)a 0.003 0.66 0.68
Vomiting symptoms 4.95 (2.86) 4.74 (2.88) 1.44 (2.08)a 2.08 (0.31)a ,0.001 1.04 (2.08)a,b 1.72 (2.14)a,b ,0.001 0.49 0.51
Total 18.76 (5.48) 19.18 (5.63) 7.06 (5.79) 12.81 (6.88)a ,0.001 6.83 (5.36)a,b 8.83 (7.42)a,b ,0.001 0.61 0.62
HADS
Anxiety symptoms 11.30 (4.39) 10.13 (3.66) 6.23 (3.09)a 10.11 (3.82) ,0.001 5.95 (2.95)a 3.73 (0.57) ,0.001 0.53 0.54
Depression symptoms 7.32 (3.46) 7.34 (3.44) 3.82 (0.58)a 7.30 (3.23) ,0.001 5.23 (2.05)a 7.16 (3.18) ,0.001 0.70 0.72
a a
Total 18.62 (6.28) 17.48 (6.81) 11.41 (4.02) 17.41 (6.25) ,0.001 11.18 (3.88) 17.18 (5.88) ,0.001 0.68 0.69
PDQ
Birth concerns 10.46 (4.65) 10.37 (4.80) 7.11 (2.94)a 10.16 (4.50) 0.004 7.00 (2.76)a 10.46 (4.04) 0.005 0.65 0.66
Body concerns 4.62 (2.51) 4.25 (2.38) 3.13 (2.01)a 4.16 (2.35) 0.001 3.23 (2.11)a 4.09 (2.84) 0.03 0.47 0.45
a a
Relationship concerns 3.55 (2.11) 2.95 (1.86) 1.46 (2.03) 2.90 (1.86) ,0.001 1.53 (2.20) 2.83 (2.43) 0.02 0.43 0.42
Total 18.65 (8.24) 17.58 (7.73) 12.72 (5.54)a 17.27 (7.16) ,0.001 12.76 (5.38)a 17.48 (7.20) ,0.001 0.59 0.59

Score Range: nausea symptoms, 0–20; vomiting symptoms, 0–12; total RINVR scores, 0–32; anxiety symptoms, 0–21; depression symptoms, 0–21; total HADS scores, 0 – 42; birth concerns, 0 –24; body concerns, 0–12; relationship concerns,
0–12; total PDQ scores, 0–42.
Post-treatment; 3 weeks after baseline, follow-up; 4 weeks after post-treatment.
Mixed-effects: Within-group values with alphabetic superscripts for each measure are statistically significant (Bonferroni test) at each phase of administration; aPost-treatment and follow-up with baseline; bPost-treatment with follow-up.
P-values present the interactions of time and group.
Effect size is calculated post hoc using Cohen’s for the experimental group.
RINVR, Rhodes index of nausea, vomiting and retching; HADS, hospital anxiety and depression scale; PDQ, prenatal distress questionnaire.

2769
2770
Table IV Subjective clinical improvement of NVP-specific problems and general health after treatment and follow-up.
Post-treatment
(N 5 41)
.......................................................................
Medical therapy plus
psychotherapy
N (%)
.............................................................................................................................................................................................
NVP-specific problem
Much or somewhat better 34 (82.9)
About the same/somewhat, 7 (17.1)
quite a lot or much worse
General health
Much or somewhat better 35 (85.3)
About the same/somewhat, 6 (14.7)
quite a lot or much worse
Post-treatment; 3 weeks after baseline, follow-up; 4 weeks after post-treatment.
Chi-square test was applied.
symptoms from pre- to post-treatment and follow-up (P , 0.05). The
results showed that, although both intensive MBCT and pyridoxine
decreased significantly the mean RINVR scores at post-treatment and
follow-up, the decrease in the medical therapy plus psychotherapy
group was significantly more than that in the medical treatment alone
group.
Psychological symptoms
Table III shows the trend of changes in the mean scores of anxiety/
depression symptoms in the two groups over the trial period. A
mixed-effects model analysis on the HADS subscales revealed a signifi-
cant interaction effect for group × time on all of the psychological symp-
toms. There were differences between the medical therapy plus
psychotherapy group and medical therapy alone group in the improve-
ment of all psychological symptoms over the period of the trial: depres-
sion (P , 0.01), anxiety (P , 0.001) and total HADS scores (P , 0.001).
A mixed-effects model analysis on each group over the period of the trial
revealed that the mean scores for depression and anxiety symptoms
improved significantly in the medical therapy plus psychotherapy group
from pretreatment through to post-treatment and follow-up. The
mean difference between baseline and post-treatment decreased for
anxiety 5.1 (95% CI, 3.2, 9.2), depression 3.5 (95% CI, 2.4, 7.3) and
total HADS 7.2 (95% CI, 4.4, 12.1). Medical therapy alone did not
improve the depression and anxiety symptoms from pretreatment
through to post-treatment and follow-up (P . 0.05).
Table III shows the trend of changes in the mean scores of pregnancy
distress in the two groups over the trial period. A mixed-effects model
analysis of the PDQ subscales revealed a significant interaction effect
for group × time for all of the psychological symptoms. There were dif-
ferences between the medical therapy plus psychotherapy and medical
therapy alone groups in the improvement of all pregnancy distress sub-
scales over the period of the trial: concerns about birth and the baby
(P , 0.01), concerns about weight/body image (P , 0.001), concerns
about emotions and relationships (P , 0.001), and total PDQ scores
(P , 0.001). A mixed-effects model analysis on each group over the
period of the trial revealed that the mean scores of pregnancy distress
Faramarzi et al.
Follow-up
(N 5 40)
.......................................................................
Medical therapy P-value Medical therapy plus Medical therapy P-value
alone psychotherapy alone
N (%) N (%) N (%)
25 (60.9) 0.004 37 (92.5) 24 (60.0) 0.002
16 (39.1) 3 (7.5) 14 (35.0)
Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019
15 (36.5) ,0.001 35 (87.5) 20 (50.0) ,0.001
26 (63.5) 5 (12.5) 20 (50.0)
decreased significantly in the medical therapy plus psychotherapy
group from pretreatment through to post-treatment and follow-up.
The mean difference between baseline and post-treatment decreased
for birth concerns 3.3 (95% confidence interval (CI), 1.3, 9.1), body con-
cerns 1.5 (95% CI, 0.9, 5.1), relationship concerns 2.1 (95% CI, 1.2, 5.9)
and total PDQ 5.9 (95% CI, 3.5, 10.6). Medical treatment did not
improve pregnancy distress from pretreatment through to post-
treatment and follow-up (P . 0.05). Medical therapy plus psychother-
apy also improved nausea/vomiting symptoms, psychological symp-
toms, and reduced pregnancy distress more than medical therapy
alone, with an effect size of 0.42 –0.72 over the trial period.
Subjective clinical changes
Different responsiveness parameters were observed for the outcomes
measured (Table IV). In terms of the subjective clinical improvement of
NVP-specific and psychological symptoms, the percentage of patients
that exceeded ‘much or somewhat better’ was higher for the experimen-
tal group at both post-treatment and follow-up. Differences between
both groups were statistically significant in all the outcomes measured
at post-treatment and follow-up in severity of nausea/vomiting symp-
toms, and anxiety and depression related health scales.
Discussion
In this parallel-group RCT, 3 weeks of medical therapy plus psychother-
apy yielded statistically and clinically significant improvements in
NVP-specific symptoms, anxiety/depression symptoms, and pregnancy
distress, compared with medical therapy alone. One month after treat-
ment, the benefits of intensive MBCT therapy on NVP-specific symp-
toms continued and there were continued improvements in the
secondary measures of anxiety/depression, and pregnancy distress in
the medical therapy plus psychotherapy group.
Several studies report links between psychological factors and NVP.
However, only a limited number of trials have evaluated psychological
interventions for NVP. Madrid et al. (2011) report four cases of
women experiencing nausea throughout their pregnancy who were
Psychotherapy and nausea and vomiting of pregnancy
treated with a brief form of hypnosis that used a psychodynamic investi-
gation of the cause of the problem. Simon and Schwartz (1999) reviewed
empirical studies of medical hypnosis (three cases studies) for treating
hyperemesis gravidarum. They suggest that medical hypnosis should
be considered as an adjunctive treatment option for women with hyper-
emesis gravidarum. They also conclude that medical hypnosis can be
used to treat common morning sickness, which is experienced by up
to 80% of pregnant women.
Some studies have compared acupressure in the improvement of NVP
symptoms. Saberi et al. (2013) report that acupressure is effective in re-
lieving nausea, vomiting, and retching. However, they conclude that
ginger is more effective than acupressure to relieve mild-to-moderate
nausea and vomiting in symptomatic pregnant women. Matthews et al.
(2010) reviewed 27 trials covering many interventions, including
acupressure, acustimulation, acupuncture, ginger, and vitamin B6 (pyri-
doxine) and several other antiemetic drugs. Evidence regarding the ef-
fectiveness of acupressure is limited. Acupuncture shows no significant
benefit to women in pregnancy. The use of ginger products may be
helpful to women, but the evidence of effectiveness is limited and not
consistent. There is only limited evidence from trials to support the
use of antiemetic drugs, like vitamin B6, to relieve mild or moderate
nausea and vomiting.
Anxiety disorders during pregnancy are highly prevalent (Chen et al.,
2010; Rezaie and Faramarzi, 2014) and are associated with serious con-
sequences for both the mother and child. The use of exposure-based
psychosocial treatments using CBT for anxiety disorders in adults in
general as well as pregnant women (especially women with NVP) has
largely been excluded from CBT research. In terms of the existence of
any potential negative short- or long-term risks associated with CBT
for pregnant women, Arch et al. (2012) argue for the safety of CBT in
pregnancy and conclude that exposure-based therapies are likely to be
safe during pregnancy, particularly relative to the alternatives. Further,
other available evidence strongly suggests that pregnant women are
likely to prefer non-pharmacological approaches to anxiety disorder
treatment, a choice that is supported by the efficacy studies comparing
medication to CBT. Arch (2014) in a US sample of pregnant (n ¼ 377)
and matched non-pregnant women (n ¼ 399) rated overall treatment
preferences and treatment credibility, concerns, and willingness to
have CBT and pharmacotherapy if suffering from anxiety. He reports
that women prefer anxiety-related treatment that includes psychother-
apy. Preference for psychotherapy alone was stronger among pregnant
(74%) than non-pregnant (47%) women. In response to treatment
descriptions, both pregnant and non-pregnant women rate CBT more
favorably than pharmacotherapy in terms of treatment willingness, cred-
ibility, and concerns; with the magnitude of this preference being
significantly greater among pregnant women.
The considerable effect MBCT was found to have, in this study, on
NVP-specific and psychological symptoms has not been reported in pre-
vious studies on other psychotherapies (such as hypnotherapy), which
may be attributable to the nature of both the therapy and the NVP con-
dition. Physical illness in NVP, as in other, established psychosomatic dis-
orders, can be conceived as an attempt to master distress, as adaptation
effort, or even as self-destruction. Selye’s theory of stress describes pos-
sible links between organ pathology and the psychosocial situation
(Klussman, 1999). Although this study is the first to apply MBCT psycho-
therapy to NVP women, we believe the substantial effect it was found to
have on nausea/vomiting symptoms may be related to the nature of the
2771
method. Anxiety and depression play an important role in increased
symptoms in women with NVP (Buckwalter and Simpson, 2002;
Tan et al., 2010). Previous clinical trials provide strong support for the
efficacy of MBCT adapted for the treatment of eating disorders
(Kristeller et al., 2006). As with many applications of mindfulness and
related meditation techniques, there is some value in framing MBCT
within a relaxation or stress management context. This is salient in rela-
tion to NVP problems, because stress and negative emotions are common
triggers of NVP symptoms (Buckwalter and Simpson, 2002). Another key
aspect of MBCT involves helping patients recognize how anxiety/depres-
sion thoughts may exacerbate their NVP symptoms. MBCT provides indi-
Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019
viduals with a heightened ability to simply observe feelings, behaviors, and
experiences, to disengage automatic and often dysfunctional reactivity,
and then to allow themselves to work with and develop wiser and more
balanced relationships with themselves, their eating, and their bodies.
This linking process may be an important therapeutic mechanism. The
focus of MBCT on emotions and thoughts may be effective because in-
creasing awareness of emotional changes and distress processes makes
improved emotional experiences possible (perhaps probable) treatment
outcomes. Thus, a release from anxiety/depression symptoms and preg-
nancy distress may improve the regulation of emotional affect and may
have central healing effects in NVP women. Thus, it seems that the coord-
ination between the method of MBCT and the nature of NVP may have
contributed to the successful results of the psychotherapy.
The strengths of our study include the fact that complete analyses
were made, taking into account the clinical importance of the observed
statistical results. We also focused on important outcomes, such as de-
pression/anxiety symptoms and pregnancy distress, and measured these
using validated questionnaires. Our study was the first clinical trial to
assess the effectiveness of MBCT psychotherapy in patients with NVP,
and thus further research would be helpful to explore whether other
psychotherapies can produce similar effects.
There were a number of limitations to our study that warrant caution
against generalizing from our results. First, the sample size was small, and
the results need to be replicated with further larger studies. A second
limitation refers to the nature of the control conditions, which did not
really compare medical treatment with MBCT. This means that we
cannot rule out that the positive effects are related to the extra time
and attention paid to patients in the psychotherapy group. Our main
concern in the study is to determine whether MBCT therapy had specific
effects, over and above those obtained from, and attributable to, the
nonspecific effects of psychotherapy. The medical therapy plus psycho-
therapy group received more treatment, and the positive results
obtained may be due to more treatment (e.g. more contact, more
support) rather than anything specific about MBCT. We did not use
the ‘placebo psychotherapy group’ to describe the psychological
control. Placebo intervention is used specifically to control for the
time, sympathy, support and attention received by the patients in the
MBCT group. In future studies, it might help to add a third group of
patients who are receiving placebo psychotherapy along with medical
treatment. Third, the RCT was an unblinded study. The participants in
the study did not remain blind to the treatment, and their treatment
expectations may, therefore, have affected the outcomes. The results
of unblinded RCTs tend to be biased toward beneficial effects. In this
study, MBCT patients groups were going through extraordinary times
and circumstance and received significantly more interaction with the
professionals during the trial. This susceptibility may contribute to the
2772
physical well-being of the women in the mindfulness group. If so, we
cannot ascribe differences between therapy groups exclusively to the
psychotherapeutic intervention. Only when both the patients and care-
givers are unaware of the treatment assignment can their desire for a
favorable outcome not potentially bias the results of the trial. Reliability
of the results of a trial is strengthened when the investigators use mechan-
isms such as an independent blinded end-points committee. Therefore,
it is important that any future trials are designed as a double-blind,
placebo-controlled study to assess the effect of the psychotherapy
in patients with NVP. Finally, it should be noted that the outcome may
only be representative of women with moderate NVP who have been
referred to obstetrics clinics.
To the best of our knowledge, as there have been no RCTs that assess
the effectiveness of adding psychotherapy to treatment with medication
in moderate NVP, we are unable to comment on the relative economic
advantages of MBCT psychotherapy. The economic impact of psycho-
logical treatment in moderate NVP, therefore, warrants further investi-
gation.
In conclusion, adding 3 weeks of psychological intervention to medical
therapy appears to be a promising approach for women with moderate
NVP. It produces positive therapeutic outcomes upon the conclusion of
treatment and 1 month after treatment. Further studies, including an
economic evaluation of the addition of psychological intervention to
standard medical therapy, would be useful. The results of the study
suggest that MBCT psychotherapy should be considered as an adjunctive
treatment option for women with moderate NVP.
Acknowledgements
The authors thank Dr. Evangelin Vangie Forondo for editing the English of
the paper. We also thank the Development Center of Clinical Research
of the Rohani Hospital of Babol for helping with the implementation of
the project.
Authors’ roles
M.F. designed the trial, monitored data collection for the whole trial,
cleaned and analyzed the data, and drafted and revised the paper. S.Y.
designed the trial, cleaned and analyzed the data, and drafted and
revised the paper. S.B. designed the intervention and data collection
tools, and drafted and revised the paper.
Funding
Infertility and Reproductive Health Research Center of the Babol univer-
sity of Medical Sciences funded this study.
Conflict of interest
None declared.
References
Abiodun OA. A validity study of the Hospital Anxiety and Depression Scale in
general hospital units and a community sample in Nigeria. Br J Psychiatry
1994;165:669 – 672.
Faramarzi et al.
Arch JJ. Cognitive behavioral therapy and pharmacotherapy for anxiety:
treatment preferences and credibility among pregnant and non-pregnant
women. Behav Res Ther 2014;52:53– 60.
Arch JJ, Dimidjian S, Chessick C. Are exposure-based cognitive behavioral
therapies safe during pregnancy? Arch Womens Ment Health 2012;
15:445 – 457.
Babaei AH, Haji Foghaha M. A randomized comparison of vitamin B6 and
dimenhydrinate in the treatment of nausea and vomiting in early
pregnancy. Iran J Nurs Midwifery Res 2014;19:199 – 202.
Baer RA. Mindfulness training as a clinical intervention: a conceptual and
empirical review. Clin Psychol Sci Pract 2003;10:125 – 143.
Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019
Buckwalter JG, Simpson SW. Psychological factors in the etiology and
treatment of severe nausea and vomiting in pregnancy. Am J Obstet
Gynecol 2002;186:S210 – S214.
Cape J, Whittington C, Buszewicz M, Wallace P, Underwood L. Brief
psychological therapies for anxiety and depression in primary care:
meta-analysis and meta-regression. BMC Med 2010;8:38 – 51.
Chen Y-H, Lin H- C, Lee H-C. Pregnancy outcomes among women with
panic disorder: do panic attacks during pregnancy matter? J Affect Disord
2010;120:258 – 262.
Chou FH, Avant KC, Kuo SH, Fetzer SJ. Relationships between nausea and
vomiting, perceived stress, social support, pregnancy planning, and
psychosocial adaptation in a sample of mothers: a questionnaire survey.
Int J Nurs Stud 2008;45:1185 – 1191.
Czeizel AE, Puhó E. Association between severe nausea and vomiting in
pregnancy and lower rate of preterm births. Paediatr Perinat Epidemiol
2004;18:253 – 259.
D’Orazio LM, Meyerowitz BE, Korst LM, Romero R, Goodwin TM. Evidence
against a link between hyperemesis gravidarum and personality
characteristics from an ethnically diverse sample of pregnant women: a
pilot study. J Womens Health 2011;20:137– 144.
Gennaro S, Shults J, Garry DJ. Stress and preterm labor and birth in black
women. J Obstet Gynecol Neonatal Nurs 2008;37:538– 545.
Gueorguieva R, Krystal JH. Move over ANOVA: progress in analyzing
repeated-measures data and its reflection in papers published in the
Archives of General Psychiatry. Arch Gen Psychiatry 2004;61:310 –317.
Kabat-Zinn J. Full Catastrophe Living: Using the Wisdom of Your Body and Mind to
face stress, Pain, and Illness. New York: Bantam Doubleday Dell Publishing,
1990.
Kim TH, Choi BM, Chin JH, Lee MS, Kim DH, Noh GJ. The reliability and validity
of the Rhodes index of nausea, vomiting and retching in postoperative
nausea and vomiting. Korean J Anesthesiol 2007;52:59–65.
Klussman R. Ongoing conflict situations and physical disease. Wien Med
Wochenschr 1999;149:318 – 322.
Kramer J, Bowen A, Stewart N, Muhajarine N. Nausea and vomiting of
pregnancy: prevalence, severity and relation to psychosocial health.
MCN Am J Matern Child Nurs 2013;38:21 – 27.
Kristeller JL. Mindfulness, wisdom and eating: applying a multi-domain model
of meditation effects. J Constructivism Hum Sci 2003;8:107– 118.
Kristeller JL, Bear R, Quillian-Wolever R. In: Baer R (ed). Mindfulness-Based
Approaches to Eating Disorders. New York: Guilford Press, 2006.
Kuo SH, Yang YH, Wang RH, Chan TF, Chou FH. Relationships between
leptin, HCG, cortisol, and psychosocial stress and nausea and vomiting
throughout pregnancy. Biol Res Nurs 2010;12:20 – 27.
Madrid A, Giovannoli R, Wolfe M. Treating persistent nausea of pregnancy
with hypnosis: four cases. Am J Clin Hypn 2011;54:107– 115.
Markl GE, Strunz-Lehner C, Egen-Lappe V, Lack N, Hasford J. The association
of psychosocial factors with nausea and vomiting during pregnancy.
J Psychosom Obstet Gynaecol 2008;29:17–22.
Matthews A, Haas DM, O’Mathúna DP, Dowswell T, Doyle M. Interventions
for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev
2010;3:CD007575.
Psychotherapy and nausea and vomiting of pregnancy
Montazeri A, Vahdaninia M, Ebrahimi M, Jarvandi S. The Hospital Anxiety and
Depression Scale (HADS): translation and validation study of the Iranian
version. Health Qual Life Outcomes 2003;28:1 – 14.
Munch S, Korst LM, Hernandez GD, Romero R, Goodwin TM. Health-related
quality of life in women with nausea and vomiting of pregnancy: the
importance of psychosocial context. J Perinatol 2011;31:10–20.
Rezaie R, Faramarzi M. Predictors of mental health during pregnancy. Iran J
Nurs Midwifery Res 2014;19:S45 – S50.
Roseboom TJ, Ravelli AC, van der Post JA, Painter RC. Maternal characteristics
largely explain poor pregnancy outcome after hyperemesis gravidarum. Eur J
Obstet Gynecol Reprod Biol 2011;156:56–59.
Saberi F, Sadat Z, Abedzadeh-Kalahroudi M, Mahboobeh Taebi M.
Acupressure and ginger to relieve nausea and vomiting in pregnancy: a
randomized study. Iran Red Crescent Med J 2013;15:854– 861.
Segal ZV, Williams J, Teasdale JD. Mindfulness-Based Cognitive Therapy for
Depression: A New Approach to Preventing Relapse. New York, NY: The
Guilford Press, 2002.
Simon EP, Schwartz J. Medical hypnosis for hyperemesis gravidarum. Birth
1999;26:248 – 254.
2773
Swallow BL, Lindow SW, Masson EA, Hay DM. Psychological health in early
pregnancy: relationship with nausea and vomiting. J Obstet Gynaecol 2004;
24:28– 32.
Tan PC, Yow CM, Omar SZ. A placebo-controlled trial of oral pyridoxine in
hyperemesis gravidarum. Gynecol Obstet Invest 2009;67:151– 157.
Tan PC, Vani S, Lim BK, Omar SZ. Anxiety and depression in hyperemesis
gravidarum: prevalence, risk factors and correlation with clinical severity.
Eur J Obstet Gynecol Reprod Biol 2010;149:153 – 158.
Uguz F, Gezginc K, Kayhan F, Cicek E, Kantarci AH. Is hyperemesis
gravidarum associated with mood, anxiety and personality disorders: a
case-control study. Gen Hosp Psychiatry 2012;34:398 – 402.
Downloaded from https://academic.oup.com/humrep/article-abstract/30/12/2764/2380392 by guest on 25 December 2019
Vutyavanich T, Wongtra-Ngan S, Ruangsri R. Pyridoxine for nausea and
vomiting of pregnancy: a randomized, double-blind, placebo-controlled
trial. Am J Obstet Gynecol 1995;173:881 – 884.
Yali AM, Lobel M. Coping and distress in pregnancy: an investigation of
medically high risk women. J Psychosom Obstet Gynaecol 1999;20:39– 52.
Wibowo N, Purwosunu Y, Sekizawa A, Farina A, Tambunan V, Bardosono S.
Vitamin B6 supplementation in pregnant women with nausea and vomiting.
Int J Gynaecol Obstet 2012;116:206 – 210.