Prof. Dan Sherman International Workshop on A.R...The Psychological Impact of Infertility Psychological Stress Distress Anxiety disorder Depressive symptoms Depression Prevalence is
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Psychological Stress and
Interventions in ART
Prof. Dan Sherman
International Workshop on A.R.T
9-13 January 2012
Introduction
The Psychological Impact of Infertility
The inability to conceive children is experienced
as a stressful and often heartbreaking situation
People with infertility suffer a great deal
Life crisis, roller-coaster of emotions
Most IVF patients say: IVF treatment is primarily
a psychological rather than a physical stressor
May have deleterious social and psychological
consequences, evolving to a true psychiatric
disorder
The Psychological Impact of Infertility
Psychological Stress Distress
Anxiety disorder
Depressive symptoms
Depression
Prevalence is 2-3 times higher relative to fertile women
Evidence: distress levels may influence
The outcome of fertility Rx
Major factor in decision to drop-out
Cause
Effect
?
Terminology
Stress - mental tension, physiological arousal
Distress - the resulting emotional suffering
Anxiety – “tense, nervous, worried”
Depression – “sad, isolated, angry, frustrated”
Psychiatric disorder
symptoms are more than an expected response
Impaired ability to function
increased risk of death, pain,
disability, or suicide
Outline
Causes of emotional stress in infertility
Prevalence and intensity of psychological distress
The biological mechanisms or the “Mind-Body
Connection”
Effect of stress on reproductive / IVF outcomes
Effect of psychological interventions on infertility
Rx & IVF outcomes
Conclusions for psychological interventions
Acupuncture & IVF outcomes
Causes of Emotional Stress
in Infertility Patients
Causes of Emotional Stress
Loss of control, Identity issues
A challenge to the fundamental desire/right to reproduce
Childlessness is (perceived as) a sign of diminished status, defectiveness, and reduced competence Damage to self-esteem and in some cultures to
core female identity - woman’s mission in life
A threat to support/survival in old age
Guilt feelings: infertility is a punishment for past sexual indiscretions, abortions or contraceptive use
Causes of Emotional Stress - Fertility Rx requires
significant life adjustments Supersedes other life aspirations, long term goals
and career choices
May become the sole focus in life
other goals and social connections are placed on hold or disrupted
Intrusion of intimacy, rigid treatment regimes, frequent testing, invasive (humiliating?) procedures
Marital distress: Loss of spontaneity, scheduling of sex, mood fluctuations, who is responsible?
Men may have transient episodes of impotence and sexual performance anxiety
Causes of Emotional Stress
Fertility Rx is also associated with
Uncertainty of treatment results
Expectations (Hope) - Disappointment cycles
Need for crucial decision-making
i.e., # of embryos
Confrontation with moral & ethical issues
i.e., 3rd party reproduction
Barriers to medical Rx, including
financial costs and limited health insurance
reimbursement
The Prevalence and Intensity
of Psychological Distress
Prevalence and Intensity of
Psychological Distress Controversy: some reviews have not found any
or noted only minor differences between infertile and fertile women
Most of the research relies on self-report questionnaires and very little on structured psychiatric interviews
Infertile patients tend to hide their true levels of anxiety a/o depression for fear that they may be found inappropriate for treatment / parenthood
Prevalence and Intensity of
Psychological Distress
Compared with general (gynecology) fertile patients, infertile women showed:
significantly higher (X2) scores on measures of depression, anxiety and hostility
11% (vs. 4%) - criteria for major depressive episode
40% (vs. 12%) – a psychiatric disorder (depression or anxiety by psychiatric interview)
Domar 1992, Downey 1992, Wright 1991, Chen 2004
Psychological Distress in IVF
In many Patients:
Depressive symptoms prior to beginning IVF cycle
the impact of repeated, unsuccessful, less
invasive forms of treatment, but may also reflect
Typically: symptoms of depression, anxiety, anger,
and isolation after unsuccessful treatment
may persist over extended periods of time Baram 1988
Psychological Distress in IVF
Impact on Drop-out Traditionally physician advise (poor prognosis) or
finances (lack of coverage) – main reasons
Recent data, from programs with full coverage:
The most commonly cited reason was the psychological stress & emotional burden (66%), followed by the perception of poor prognosis
Pretreatment levels of depression were highly predictive of patient drop-out behavior after only one cycle
Hammarberg 2001, Olivius 2004, Rajkhowa 2006
Psychological Distress in IVF
Who is at Risk and When?
Pretreatment psychological problems
Anxiety greater in the partner with the problem
Women in abusive relationships, poor partner
communication, lack of family support
Women with functional/unexplained (vs. organic)
infertility
Certain personality characteristics:
Dependency, helplessness, neuroticism, self-criticism,
active-avoidance coping style
Cause
Effect
?
The Biological Explanation: Stress and Infertility
The Neuro-endocrine pathways of stress
Stress and Reproductive
Outcome
Studies on stress exposure and
reproductive outcomes
All epidemiological studies (1980-2007)
A direct causal link or a statistically
significant association between stress
exposure and human reproductive
failure was found in
7/9 studies that met inclusion criteria
3/4 excluded studies Nakamura et al: Stress and reproductive failure: past notions, present insights
and future directions. J Assist Reprod Genet (2008) 25:47–62
The impact of stress on reproductive
performance
An association between increased levels of psychological stress and impaired reproductive performance
The level of precision in a cause-effect relationship is low
Stress measurements - subjective
No consensus in measuring stress levels
The evidence is limited and not consistent across all studies
Homan: The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: a review. Hum Reprod Update 2007
Stress reduces conception probabilities across the
fertile window: evidence in support of relaxation
Prospective cohort: 274 women (18-40 ys old)
who were attempting pregnancy
Observed for 6 cycles or until pregnancy
Collected basal saliva samples* on day 6 of
each cycle, and used urinary LH (from day 6,
for 20 days) to identify ovulation
* for cortisol (HPA) and a-amylase (SMA) as bio-
markers of perceived psychosocial stress
HPA=hypothalamic-pituitary-adrenal axis
SAM =sympathetic medullar system (catecholamines)
Stress reduces conception probabilities across the
fertile window: evidence in support of relaxation
Alpha-amylase but not cortisol were negatively
associated with fecundity (time-to-pregnancy)
after adjusting for the couples’ ages,
intercourse frequency, and alcohol
consumption
Buck Louis, Fertil Steril 2010
Statistically significant reductions in the probability of conception across the fertile window for women whose salivary a-amylase were in the upper quartiles in comparison with women in the lower quartiles
Buck Louis, Fertil Steril 2010
Impact of Stress on IVF
Outcome
Los Angeles Times:
Worry can affect IVF success October 2009
Impact of Stress on IVF Outcome
Review of 24 Studies Domar, UpToDate 2008
16 (2/3) found a significant relationship between pre-procedure distress and subsequent pregnancy rates
3 noticed a trend
4 reported no relationship
1 inadequate data to draw any conclusions
The interpretation is limited by methodological flaws:
Measures of distress taken at different stages of the Rx
Lack of adjustment for the potential impact of negative feedback (patients are aware of U/S & Lab results)
Small sample sizes
Baseline (pre-Rx) stress and IVF or GIFT
Outcome Klonoff-Cohen 2001, 2004
Prospective study using several stress scales
151 participants (for 66% - 1st Rx cycle)
completed a battery of psychological questionnaires
at their first clinic visit and at the time of their
procedure
The baseline level of stress was significantly
correlated with:
# of oocytes retrieved and fertilized
Pregnancy and live birth rates
Birth weight
Baseline (pre-Rx) stress and IVF or GIFT
Outcome Klonoff-Cohen 2001, 2004
The stress level on the day of the
procedure was significantly related only to the
# of oocytes retrieved and fertilized
Multivariate analyses, controlling for other
important factors (i.e, age, # of previous Rx…):
higher baseline stress/anxiety scores
increased the odds of “no-live birth”
Conclusion: baseline stress predisposes
women to negative reproductive outcomes
Lifestyle habits and IVF: what is known
and unknown Klonoff-Cohen 2005
24 prospective, 15 cross-sectional, 4 retrospective
Only 7 used fertile women as comparison
13 employed multivariate analyses and adjusted for
potential confounders
The evidence that psychological stress during
treatment was associated with negative IVF
outcomes is suggestive but insufficient
due to heterogeneity of studies (stress instruments
and IVF endpoints)
Pretreatment Emotional Distress and
Pregnancy after ART Boivin BMJ 2011
14 Prospective Psychological studies 1985-2010
3583 women evaluated for emotional distress before an ART cycle
Pretreatment level of distress was not associated with treatment outcome
Pregnancy = +hCG, +FHS, LB
Moderate publication bias - suspected
Emotional distress caused by fertility or other life events will not compromise the chance of becoming pregnant…
Emotional distress in infertile women and failure of ART: meta-analysis of prospective psychosocial studies. Boivin, BMJ 2011
Psychological Interventions
for Infertility
Psychological Interventions
for Infertility Patients
Individual - Couple - Group
Counseling (emotional expression-support)
Cognitive-behavioral therapy (change the way
you think, feel and behave)
Educational (knowledge, skills training)
Stress reduction / Relaxation
Psychodynamic/-analytic
Psychological Interventions in Infertility
The important outcomes
Improvement in mental health measures:
Anxiety
Depression
Mental distress
Interpersonal functioning
Infertility-specific stress
Increased pregnancy rate among infertile
couples
3 systematic reviews of published studies
Boivin 2003, de Liz & Strauss 2005, Hammerli 2009
A review of psychosocial interventions in
infertility Boivin 2003
380 studies reviewed: 1966-2002
25 included in the analysis,
but only 11 (44%) “better quality
research”
Appropriate control group (9/11 randomized)
Routine care, only general support
inappropriate=drop-outs or refuse to attend
Pre-to-post intervention comparison
(n=15)
A review of psychosocial interventions in
infertility Boivin 2003
Positive effect (improvement) on:
Anxiety in 8/13 studies
Depressive symptoms in 5/13 studies
Interpersonal functioning in 3/11
Infertility related stress in 6/6 studies
Target behavior (sexual) in 10/10 studies
No clear efficacy for pregnancy rate:
Increase 6-18 mths after intervention in 3/8 “better
quality” studies (controlled)
Group & Individual/Couple Psychotherapy in
Infertility – A Meta-analysis de Liz 2005
66 prospective studies: 1979-2003
22 studies with quantitative data for computing ES
(treatment effect) – controlled & uncontrolled
Both types of psychotherapies led to
Decreased anxiety and depressive
symptoms
Higher mean pregnancy rates:
45% (18 studies) vs. 14% in controls (6 studies)
Group & Individual/Couple Psychotherapy in
Infertility – A Meta-analysis de Liz 2005
Conclusion:
Psychotherapy reduces anxiety & depression for infertile patients and possibly enhances conception success
But because of the possibility of biasing factors, a definite connection cannot be made
Many of the studies did not have a control group or used randomization
Only RCT* may truly eliminate systematic differences between the groups, which are not related to Rx
*Randomized-Controlled study
Psychological Interventions for Infertility
A Meta-analysis Hammerli 2009
384 articles: 1978-2007
Only prospective controlled studies (n=21)
Controls either on waiting lists or routine care
Only 12 (of 21) randomized (RCT)
No significant effect on mental health outcomes (depression, anxiety, distress)
Positive impact on pregnancy rate (RR=1.42)
99%CI=1.02-1.96
Subgroup analysis: significant effect only in non-ART
Psychological Interventions for Infertility
A Meta-analysis Hammerli 2009
Effect on pregnancy rate
Psychological Interventions
for IVF
Psychological Interventions for IVF
Randomized, controlled studies (RCT)*
Chan 2006 (n=227) Eastern body-mind-spirit 4 group sessions
Lower anxiety score, higher PR (trend)
Connolly 1993 (n=152) 3 counseling sessions – No effect
De Klerk 2005 (n=84) 3 sessions with social worker – No effect
Emery 2003 (n=100) Pre IVF Counseling – No effect
Domar 2009 (n=97) 2011 (n=143) 10 sessions mind-body program – Higher PR
*Controls: Routine care
Psychological Interventions for IVF
Randomized, controlled studies (RCT)*
Shu-Hsin 2003 (n=132)
Nursing crisis on day 3 (Video, self hypnosis, relaxation,
CBT)
Positive effects in relieving psycho-social responses
Tarabusi 2004 (n= 50)
12 CBT sessions while waiting to start IVF
Decreased stress
Terzioglu 2001 (n=60)
Daily escort & support by nurse
Lower anxiety & depression, Higher PR
*Controls: Routine care
Psychological Interventions for IVF
Non Randomized, Controlled Studies
McNaughton-Cassill 2002 (n=50) – Prospective
Biweekly support group (incl. CBT)
Decreased anxiety in those who opted to
participate
Levitas 2006 (n=98 & 96 cycles) – Case-Control
Hypnosis during ET – Higher PR
Psychological Interventions - Summary
Few – Properly controlled studies
The vast majority – non-randomized
Significant heterogeneity in types & duration of the interventions
Skill-based maybe more effective
>6 sessions – greater positive effect
Problems to do high quality research
Funding, Patient recruitment & attrition…
Need to control for numerous factors (PR)
Need for large sample sizes to be appropriately powered
Psychological Stress & Interventions for ART
Conclusion - I
Infertility & IVF are stressful
Some of our patients suffer emotionally and some
are sick
A cause-effect relationship between stress and
infertility/reproductive failure
Biological evidence is good
Epidemiological evidence is suggestive
but not conclusive
Psychological Stress & Interventions for ART
Conclusion - II
Psychological interventions for
infertility
Make sense since patients are stressed
Most studies show that treated patients feel
better
Controlled studies suggest that
they result in higher PR,
but probably not in ART
What should we offer ? What patients want from us ?
Evidence-based Medicine
Randomized controlled trials
Effects of acupuncture on
IVF success rates
Systematic reviews and meta-analyses
Effects of acupuncture on IVF: Systematic
review and meta-analysis Manheimer BMJ 2008
RCTs: needle acupuncture within 1 day of ET
Controls: sham acupuncture or no adjuvant Rx
1966-2007 Jan
7 of 108 potentially relevant reports
1366 women undergoing IVF
Little clinical heterogeneity
The results were robust to sensitivity analyses
on study validity variables
Complementing ET with acupuncture was
associated with significant and clinically relevant
improvements in:
OR 95%CI NNT Trials
Clinical pregnancy 1.65 1.27-2.14 10 (7-17) 7
Ongoing pregnancy1.87 1.4-2.49 9 (6-15) 5
Live birth 1.91 1.39-2.64 9 (6-17) 4
Effects of acupuncture on IVF: Systematic review and meta-analysis
Manheimer BMJ 2008
Acupuncture in the management of
subfertility: Systematic review
English and Chinese databases
1966 – 2006 Aug
10 RCTs
An effective alternative for pain relief during
oocyte retrieval
The IVF pregnancy rate is significantly
increased, especially when acupuncture is
administered on the day of ET (5 trials)
Yu Ng Fertil Steril 2008
Acupuncture in IVF: Systematic review &
meta-analysis El-Toukhy BJOG 2008
RCTs: 1966-2008 Jan
Controls: sham acupuncture or no adjuvant Rx
Needle or laser acupuncture performed:
around TVOR* - 5 trials (n=877)
RR= 1.06, 95%CI=0.82–1.37, P=0.65
around ET - 8 trials (n=1623)
RR=1.23, 95%CI=0.96–1.58, P=0.1
No difference in the clinical pregnancy rates
*transvaginal oocyte retrieval
The impact of acupuncture on ART
outcome El-Toukhy Curr Opin Obstet Gynecol 2009
RCTs: 1966-2008 Dec
Controls: sham acupuncture or no adjuvant Rx
Needle acupuncture performed around ET
9 trials (n=1993): 3 only conference abstracts
No signicant difference in clinical pregnancy rate
RR=1.16, 95%CI=0.92–1.48, P=0.22
Significant clinical & statistical heterogeneity
Currently available literature does not provide sufficient evidence that adjuvant acupuncture, (around TVOR or ET) improves IVF outcome
Acupuncture and assisted conception
Cheong, Cochrane 2009
English and Chinese databases
13 RCTs (n=2209), 1966 – 2007
Acupuncture
Around OR - 5
On ET day only – 6
On ET + 2-3 days later - 2
Controls: No Rx, Sham needles, Acupoints
unrelated to fertility
Acupuncture and assisted conception
Cheong, Cochrane 2009
Evidence of benefit for livebirth rate when
acupuncture on ET day
OR=1.86, 95%CI=1.29-2.77
but not when it is performed 2-3 days after ET
OR 1.79, 95%CI=0.93-3.44
No evidence of benefit on pregnancy outcomes
when acupuncture is performed around OR
But this may be attributed to placebo effect
and the small number of women in the trials
Acupuncture & IVF success rates - Summary Author/Journal OR (n) ET (n) Meta-analysis Result
Manheimer BMJ 2008
---- 7 (1366)
Increased PR & LBR for ET (OR=1.9)
Yu Ng Fertil Steril 2008
5 (900)
5 (1113)
Increased PR for both, Especially for ET (OR=1.8)
El Toukhy BJOG 2008 Curr Opin 2009
5 (877)
9 (1993) No Sig Difference
Choeng Cochrane 2009
5 (868)
8 (1022)
Increased PR & LBR for ET (OR=1.9), but NS for OR
RCTs (1966-2009) assessing Acupuncture around Oocyte Retrieval (OR) & Embryo Transfer (ET); n= no. of patients, PR=Pregnancy rate, LBR=Livebirth rate
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