Prof. Dan Sherman International Workshop on A.R...The Psychological Impact of Infertility Psychological Stress Distress Anxiety disorder Depressive symptoms Depression Prevalence is

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


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


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


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


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


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


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


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


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


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


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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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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